Comprehensive Physiology Wiley Online Library

Targeted Delivery of Hormones to Tissues by Plasma Proteins

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Abstract

The sections in this article are:

1 Organ Physiology of Solute Exchange Through Capillary Walls
1.1 Quantitation of Capillary Solute Transport: Kety‐Renkin‐Crone Equation
1.2 Capillary Geometry, Organ Blood Flow, and Capillary Transit Times
1.3 Capillary Membrane Permeability
2 Capillary Physiology of Steroid and Thyroid Hormone Transport
2.1 Plasma Protein–Binding Kinetics
2.2 Dissociation‐Limited Transport
2.3 Enhanced Dissociation Mechanism of Plasma Protein–Mediated Transport
2.4 Transcapillary Transport of Protein–Hormone Complex
2.5 Physiology‐Based Model of Cellular Bioavailable Hormone
2.6 Experimental Attempts to Measure Free Cellular Hormone
3 Molecular Physiology of Hormone‐Binding Plasma Proteins
3.1 Albumin
3.2 Prealbumin (Transthyretin)
3.3 Thyroid Hormone–Binding Globulin
3.4 Corticosteroid‐Binding Globulin
3.5 Sex Hormone–Binding Globulin
3.6 α1‐Acid Glycoprotein (Orosomucoid)
4 Summary
Figure 1. Figure 1.

The role of hormone‐binding plasma proteins in the targeted delivery of hormones to tissues in vivo emerges from a fusion of two otherwise separate disciplines: capillary physiology and protein–ligand mass action–binding equilibria.

Figure 2. Figure 2.

The driving force in nuclear receptor hormone occupancy is the concentration of cellular free (exchangeable) hormone, which is directly proportional to the in vivo capillary bioavailable (exchangeable) hormone. Capillary bioavailable hormone, therefore, is the link between hormonal secretion and hormonal action/receptor occupancy. Although in vitro measurements of free hormone in blood reflect the concentration of free hormone in systemic (arterial or venous) circulation, in vivo methods must be employed to estimate the capillary bioavailable hormone. [From Pardridge 170 with permission.]

Figure 3. Figure 3.

The nuclear receptor dissociation constant (KD) for estradiol or testosterone approximates the concentration of albumin‐bound estradiol or testosterone but is log orders greater than the concentration of free estradiol or testosterone measured in vitro. [From Pardridge 170 with permission.]

Figure 4. Figure 4.

Delivery of hormones to tissues in vivo from the circulating plasma protein–bound pool may be viewed within the context of three distinct models: the dissociation‐limited model, the enhanced dissociation model, and the model of receptor‐mediated uptake of hormone–plasma protein complex. If the latter two models are operative, then the cellular free hormone is predicted by in vitro measurements of plasma protein–bound hormone. Conversely, when the dissociation‐limited model is operative, free cellular hormone is predicted by the free hormone measured in vitro.

Figure 5. Figure 5.

A: Structures of steroid hormones with emphasis on the polar function of groups that form hydrogen bonds with water. The hydrogen bond number (N) is given in parentheses and is equal to the total number of hydrogen bonds formed between solvent water and the individual steroid molecule. B: Brain uptake index of five different [3H]‐labeled steroid hormones is shown as means ± SE (n = 3–5 rats per point). [From Pardridge 168 and Pardridge and Mietus 184 with permission.]

Figure 6. Figure 6.

Unidirectional extraction of [3H]‐testosterone by rat brain is plotted vs. the concentration of bovine albumin present in carotid arterial injection solution. Experimentally observed extraction values are represented by closed circles (mean ± SE, n = 3–6 animals per point). Extraction values predicted by fitting the experimental data to the KRC equation are shown by open circles, and curve fitting gives the two parameters k3t (plasma to tissue influx by time) and (in vivo dissociation constant); t = 1/k10. Dashed line represents extraction values predicted by substituting into the KRC equation the albumin concentration, the k3t product, and the in vitro albumin–testosterone dissociation constant, KD = 53 ± 1 μM. Therefore, the dashed curve gives the expected inhibition of testosterone transport caused by hormone binding to albumin if testosterone was not available for transport into brain from the circulating albumin‐bound pool. However, since albumin‐bound testosterone is available via an enhanced dissociation mechanism, the upper curve is observed and the in vivo (2500 ± 700 μM) is much greater than the KD in vitro. [From Pardridge and Landaw 179 with permission.]

Figure 7. Figure 7.

Three‐dimensional structure of albumin as deduced from the primary amino‐acid sequence by Brown 22, 23. Albumin is composed of three domains and six hemicylinders. Ligand‐binding sites are interiors of the six hemicylinders of the albumin molecule. This model illustrates the high flexibility of albumin, and a marked increase in ligand dissociation is expected with a slight uncoiling caused by conformational changes about the binding site. Conformational changes are ligand‐ and tissue‐specific. For example, steroid or thyroid hormone dissociation from albumin is enhanced in brain capillaries, whereas propranolol or lidocaine dissociation is not (Table 5). Conversely, the dissociation of propranolol or lidocaine from albumin is markedly enhanced in the liver microcirculation.

Figure 8. Figure 8.

A: Percent extraction (ET) of inulin and three plasma proteins across the rat prostate gland microvasculature following a single arterial injection. Data are means ± SE (n = 3–7 rats per point). The ET values of albumin, transferrin, and inulin are comparable, whereas there is a marked increase (P < 0.05) of the prostatic extraction of testosterone‐binding globulin (TeBG). B: Darkfield micrograph of thaw‐mount autoradiogram of rat ventral prostate gland obtained 60 s after a descending aortic infusion of [3H]‐testosterone bound to the sex hormone–binding globulin (SHBG) in human pregnancy serum. These studies show rapid exodus of the [3H]‐testosterone–SHBG complex from prostatic microvessels and rapid distribution into the stromal compartment of the prostate gland. Conversely, when [3H]‐testosterone was infused in buffer without SHBG, the steroid molecule uniformly distributed over both the stromal and epithelial compartments. [From Ellison and Pardridge 55 and Sakiyama et al. 225 with permission.]

Figure 9. Figure 9.

A: Photomicrograph of isolated microvessels obtained from 28‐day‐old rabbit brain. These capillaries were used in radioreceptor assays to probe for the presence of plasma protein–specific receptors. B, left: Binding of [3H]‐testosterone‐binding globulin (TeBG) at 37°C to capillaries isolated from either 28‐day‐old (open circles) or adult (triangles) rabbits. Inclusion of 50% 28‐day‐old rabbit serum results in a marked diminution in the uptake of [3H]‐TeBG by capillaries isolated from 28‐day‐old rabbits. B, right: Uptake of [3H]‐albumin by capillaries isolated from 28‐day‐old rabbit brain is plotted vs. incubation time in the absence (closed circles) or presence (open circles) of a 50% dilution of 28‐day‐old rabbit serum. Residual uptake of [14C]‐sucrose, an extracellular fluid marker, is also shown. [From Pardridge et al. 176 with permission.]

Figure 10. Figure 10.

A: Steady‐state model of testosterone transport through the brain capillary wall and into brain cells. Pools of globulin‐bound, albumin‐bound, and free ligand in the systemic circulation are denoted as GL°, AL°, and LF°, respectively; pools of globulin‐bound, albumin‐bound, and plasma bioavailable hormone in the brain capillary are denoted as GL, AL, and LF, respectively. Pools of free and cytoplasmic bound steroid hormone in brain cells are denoted as LM and PL, respectively; t is mean capillary transit time in brain. B: Predicted steady‐state concentrations of testosterone in the various pools of the brain capillary and in brain cells. Pool sizes represent the basal state, which is simulation 1 in Table 9. The concentration of free cytosolic testosterone in brain cells is predicted to approximate the concentration of albumin‐bound hormone in the circulation but is more than tenfold greater than the concentration of free hormone measured in vitro by equilibrium dialysis. [From Pardridge and Landaw 180 with permission.]

Figure 11. Figure 11.

A: Steady‐state model of triiodothyronine transport in the liver microcirculation in vivo. Rate constants and hormone pools are defined in Table 10. B: The parameters in Table 10 were substituted into the steady‐state model equation using a program in BASIC to generate the predicted pool‐size concentrations shown in the figure, which correspond to simulation 1 of Table 11. GL°, AL°, and LF°: pools of globulin‐bound, albumin‐bound, and free ligand, respectively. GL, AL, and LF: pools of globulin‐bound, albumin‐bound, and plasma available hormone, respectively. LM and PL, pools of free and cytoplasmic bound thyroid hormone, respectively. [From Pardridge 173 and Pardridge and Landaw 181 with permission.]

Figure 12. Figure 12.

A: Fractions of free plus albumin‐bound testosterone and estradiol in vitro and bioavailable testosterone and estradiol in rat salivary gland in vivo are compared, showing that sex hormone–binding globulin (SHBG)‐bound estradiol, but not SHBG‐bound testosterone, is readily available for transport into rat salivary gland. In addition, albumin‐bound testosterone or estradiol is bioavailable in salivary gland capillaries. These in vivo measurements were made at 15 s after a single carotid artery injection of [3H]‐hormone mixed in human female serum. This short period is sufficient to allow for rapid distribution of hormone into the glandular epithelium, as shown by the autoradiographic studies in B. [From Pardridge 170 with permission.] B: Thaw‐mount autoradiogram of rat salivary gland removed 15 s after single carotid artery injection of [3H]‐estradiol dissolved in Ringer‐HEPES buffer containing 0.1 g/dl bovine albumin. The [3H]‐estradiol is found throughout the gland, with concentration over the salivary gland ductules. The tissue was counterstained after autoradiography with methylgreen‐pyronin. [From Cefalu et al. 28 with permission.] C: One‐dimensional thinlayer chromatographic separation of brain, cervical lymph node, and salivary gland homogenates of tissue obtained 60 s after a single carotid artery injection of [3H]‐testosterone (50 μCi/ml) in Ringer‐HEPES buffer containing 0.1 g/dl bovine albumin. Migration of testosterone or several other metabolites in the one‐dimensional system is shown. The minor peak in the brain and lymph node studies that co‐migrated with androstenedione (peak 2) represents an impurity in the isotope, as this was found also in the [3H]‐testosterone obtained from the manufacturer. The data show that while testosterone is rapidly metabolized in salivary gland, there is no significant metabolism in the whole brain or lymph node within 60 s after administration in vivo. [From Cefalu et al. 28 with permission.]

Figure 13. Figure 13.

Amino‐acid sequence of bovine serum albumin, displayed in a model showing the linking of cysteines to form multiple loops as proposed by Brown 22.

Figure 14. Figure 14.

Three‐dimensional structure of human serum albumin predicted from X‐ray diffraction studies. The amino (N) and carboxyl (C) termini are shown. The six different putative binding sites on the albumin molecule are shown, designated IA, IB, IIA, IIB, IIIA, and IIIB. The principal drug‐binding sites on albumin are IIA and IIIA. [From Carter and He 26 with permission.]

Figure 15. Figure 15.

Approximate amino‐acid residues comprising the six binding domains in serum albumin. [Drawn from data of Carter and He 26 with permission.]

Figure 16. Figure 16.

Unidirectional extraction of [125I]‐thyroxine (T4) into rat liver in vivo is shown for three types of portal vein injection vehicles: Ringer‐HEPES buffer plus 0.1 g/100 dl bovine albumin, normal human serum, or serum obtained from patients with familial dysalbuminemic hyperthyroxinemia (FDH) in the presence of 0 or 25 μM unlabeled T4, and rabbit anti‐T4 antiserum. Extraction of T4 following portal vein injection of Ringer‐HEPES buffer represents the situation when approximately 100% of T4 is available for extraction by hepatocytes; extraction of T4 by liver following portal vein injection of the isotope dissolved in the T4 antiserum represents the baseline extraction when the amount of injected T4 available for extraction by hepatocytes is essentially nil. Horizontal bars represent the mean ± one standard deviation for the extraction of T4 in either Ringer's solution or the T4 antiserum. [From Cefalu et al. 29 with permission.]

Figure 17. Figure 17.

Stereo view of the three‐dimensional structure predicted from X‐ray diffraction for the prealbumin homotetramer. [From Blake and Oatley 13 with permission.]

Figure 18. Figure 18.

A: Extraction of [125I]‐thryoxine (T4) into rat liver following portal vein injection of the isotope dissolved in three different solutions: Ringer‐HEPES buffer containing 0.1 g/dl bovine albumin (upper horizontal bar), control or thyroid hormone–binding globulin (TBG)–deficient human serum or normal rat serum (closed circles), T4‐specific rabbit antiserum (lower horizontal bar). Extractions obtained following injection of Ringer's solution or T4 antiserum represent the hepatocyte extraction when approximately 100% and 0%, respectively, of labeled hormone is available for transport into liver. Horizontal bars represent mean ± SE (n = 3–6 rats per point). The number of subjects in each category is shown in parentheses. B: Extraction of [125I]‐T4 by rat liver in vivo is plotted vs. the concentration of human prealbumin in the portal vein injection solution. Human prealbumin and [125I]‐T4 were mixed with either 5 or 0.1 g/dl bovine albumin or 5 g/dl dextran (65,000 daltons). Dashed line represents the extraction of T4 predicted on the basis of the bound T4 fraction as measured in vitro by equilibrium dialysis at each concentration of prealbumin. All concentrations of human prealbumin (0.01–0.3 mg/ml) bound more than 96% of T4 in vitro. Solid horizontal line represents hepatic extraction of T4 in the presence of a 10% T4 antiserum. [From Pardridge et al. 188 with permission.]

Figure 19. Figure 19.

Heterogeneity of thyroid hormone–binding globulin (TBG) structure and function Right: Extraction of [125I]‐thyroxine (T4) or [125I]‐triiodethyronine (T3) by rat liver is plotted vs. the type of serum added to the portal vein injection solution. Plasma‐free solutions contain 0.1 g/dl bovine albumin; T4‐, or T4‐specific antiserum solutions were diluted to 10%. All other samples were injected at 67% serum solutions. Each point represents a different patient, volunteer, or animal. Boxes represent the mean ± SD. Normal, human, and cord samples were obtained from both females and males. BCP, birth control pills. Left: Autoradiogram of [125I]‐T3 or [125I]‐T4 bound to TBG isoforms, albumin isoforms, and prealbumin in serum from normal male subjects, cirrhotic male patients, pregnant subjects, and normal female subjects following separation by isoelectric focusing. The pH values of the gel are shown in the ordinate of the figure. [From Pardridge 173 with permission.]

Figure 20. Figure 20.

A: Brain uptake index (BUI) for [3H]‐testosterone and [3H]‐estradiol relative to [14C]‐butanol is shown for five to nine patients in seven clinical conditions. Vertical rectangles are means ± SD; horizontal line is mean of testosterone or estradiol BUI in absence of plasma proteins. BCP, birth control pill–treated women; PMP, postmenopausal women. B: Reciprocal of BUI for [3H]‐testosterone (T) and [3H]‐estradiol (E2) is plotted vs. the level of sex hormone–binding globulin (SHBG) in human serum. Data for BUI are shown in A. P, pregnancy; B, birth control pills; T, thin postmenopausal female; F, normal follicular phase female; O, obese postmenopausal female; M, normal male; H, hirsute female. Data obtained by linear regression are shown in inset for both plots. [From Pardridge et al. 186 with permission.]

Figure 21. Figure 21.

In vitro free plus albumin‐bound, in vivo brain bioavailable, and in vivo liver bioavailable fractions for human male serum for three steroid hormones. [From Pardridge 171 with permission.]

Figure 22. Figure 22.

Metabolic clearance rate (MCR) and transport clearance rate (TCR) ratios for testosterone (T)/dihydrotestosterone (DHT) are compared for humans and rabbits. Human TCR ratio was measured in rat brain using human male serum. Rabbit TCR ratio was measured in rabbit uterus using rabbit serum 1. Human and rabbit MCR ratios were reported by Vermeulen and Andó 270 and Mahoudeau et al. 140, respectively. The T/DHT MCR ratio in the rhesus monkey 231 is virtually identical to the ratio for humans 270.

Figure 23. Figure 23.

A: Rat brain extraction of [3H]‐testosterone or [3H]‐estradiol after carotid arterial injection of labeled hormone mixed in either male cirrhotic or control human male serum. Rectangles represent means ± SD. The data show that unidirectional testosterone extraction by brain is decreased 33% (P < 0.0025) using cirrhotic serum, and this parallels a 2.6‐fold increase in sex hormon–binding globulin (SHBG) and a 40% decrease in serum albumin in cirrhosis. However, unidirectional clearance of estradiol by rat brain was not decreased using cirrhotic serum, despite the marked increase in SHBG, the decrease in albumin, and the 41% decrease in the non‐SHBG‐bound fraction of estradiol in cirrhosis. Brain bioavailable estradiol using cirrhotic serum, 54 ± 4%, exceeds non‐SHBG‐bound estradiol, 36 ± 6%, in cirrhotic serum, indicating that SHBG‐bound estradiol is available for transport into brain from plasma protein–bound pools in cirrhotic serum. Conversely, SHBG‐bound estradiol was not available for transport into brain when serum was obtained from other clinical groups (Fig. 20). [From Sakiyama et al. 224 with permission.]

B: Isoelectric focusing separation of [3H]‐testosterone‐and [3H]‐estradiol‐binding isoforms of SHBG in concanavalin‐A–glycoprotein fraction of a cirrhotic male serum pool and a normal male serum pool. The pH values of the gel are shown by a diagonal line in the bottom half of the figure. C: Profiles of estradiol‐ or testosterone‐binding isoforms of SHBG from B are replotted to allow direct comparison of results between normal male and cirrhotic male serum pools. The pH profile is shown by the diagonal line. [From Terasaki et al. 253 with permission.]

Figure 24. Figure 24.

A: Rat brain extraction of [3H]‐testosterone or [3H]‐estradiol after carotid arterial injection of labeled hormone mixed in either male cirrhotic or control human male serum. Rectangles represent means ± SD. The data show that unidirectional testosterone extraction by brain is decreased 33% (P < 0.0025) using cirrhotic serum, and this parallels a 2.6‐fold increase in sex hormon–binding globulin (SHBG) and a 40% decrease in serum albumin in cirrhosis. However, unidirectional clearance of estradiol by rat brain was not decreased using cirrhotic serum, despite the marked increase in SHBG, the decrease in albumin, and the 41% decrease in the non‐SHBG‐bound fraction of estradiol in cirrhosis. Brain bioavailable estradiol using cirrhotic serum, 54 ± 4%, exceeds non‐SHBG‐bound estradiol, 36 ± 6%, in cirrhotic serum, indicating that SHBG‐bound estradiol is available for transport into brain from plasma protein–bound pools in cirrhotic serum. Conversely, SHBG‐bound estradiol was not available for transport into brain when serum was obtained from other clinical groups (Fig. 20). [From Sakiyama et al. 224 with permission.]

B: Isoelectric focusing separation of [3H]‐testosterone‐and [3H]‐estradiol‐binding isoforms of SHBG in concanavalin‐A–glycoprotein fraction of a cirrhotic male serum pool and a normal male serum pool. The pH values of the gel are shown by a diagonal line in the bottom half of the figure. C: Profiles of estradiol‐ or testosterone‐binding isoforms of SHBG from B are replotted to allow direct comparison of results between normal male and cirrhotic male serum pools. The pH profile is shown by the diagonal line. [From Terasaki et al. 253 with permission.]



Figure 1.

The role of hormone‐binding plasma proteins in the targeted delivery of hormones to tissues in vivo emerges from a fusion of two otherwise separate disciplines: capillary physiology and protein–ligand mass action–binding equilibria.



Figure 2.

The driving force in nuclear receptor hormone occupancy is the concentration of cellular free (exchangeable) hormone, which is directly proportional to the in vivo capillary bioavailable (exchangeable) hormone. Capillary bioavailable hormone, therefore, is the link between hormonal secretion and hormonal action/receptor occupancy. Although in vitro measurements of free hormone in blood reflect the concentration of free hormone in systemic (arterial or venous) circulation, in vivo methods must be employed to estimate the capillary bioavailable hormone. [From Pardridge 170 with permission.]



Figure 3.

The nuclear receptor dissociation constant (KD) for estradiol or testosterone approximates the concentration of albumin‐bound estradiol or testosterone but is log orders greater than the concentration of free estradiol or testosterone measured in vitro. [From Pardridge 170 with permission.]



Figure 4.

Delivery of hormones to tissues in vivo from the circulating plasma protein–bound pool may be viewed within the context of three distinct models: the dissociation‐limited model, the enhanced dissociation model, and the model of receptor‐mediated uptake of hormone–plasma protein complex. If the latter two models are operative, then the cellular free hormone is predicted by in vitro measurements of plasma protein–bound hormone. Conversely, when the dissociation‐limited model is operative, free cellular hormone is predicted by the free hormone measured in vitro.



Figure 5.

A: Structures of steroid hormones with emphasis on the polar function of groups that form hydrogen bonds with water. The hydrogen bond number (N) is given in parentheses and is equal to the total number of hydrogen bonds formed between solvent water and the individual steroid molecule. B: Brain uptake index of five different [3H]‐labeled steroid hormones is shown as means ± SE (n = 3–5 rats per point). [From Pardridge 168 and Pardridge and Mietus 184 with permission.]



Figure 6.

Unidirectional extraction of [3H]‐testosterone by rat brain is plotted vs. the concentration of bovine albumin present in carotid arterial injection solution. Experimentally observed extraction values are represented by closed circles (mean ± SE, n = 3–6 animals per point). Extraction values predicted by fitting the experimental data to the KRC equation are shown by open circles, and curve fitting gives the two parameters k3t (plasma to tissue influx by time) and (in vivo dissociation constant); t = 1/k10. Dashed line represents extraction values predicted by substituting into the KRC equation the albumin concentration, the k3t product, and the in vitro albumin–testosterone dissociation constant, KD = 53 ± 1 μM. Therefore, the dashed curve gives the expected inhibition of testosterone transport caused by hormone binding to albumin if testosterone was not available for transport into brain from the circulating albumin‐bound pool. However, since albumin‐bound testosterone is available via an enhanced dissociation mechanism, the upper curve is observed and the in vivo (2500 ± 700 μM) is much greater than the KD in vitro. [From Pardridge and Landaw 179 with permission.]



Figure 7.

Three‐dimensional structure of albumin as deduced from the primary amino‐acid sequence by Brown 22, 23. Albumin is composed of three domains and six hemicylinders. Ligand‐binding sites are interiors of the six hemicylinders of the albumin molecule. This model illustrates the high flexibility of albumin, and a marked increase in ligand dissociation is expected with a slight uncoiling caused by conformational changes about the binding site. Conformational changes are ligand‐ and tissue‐specific. For example, steroid or thyroid hormone dissociation from albumin is enhanced in brain capillaries, whereas propranolol or lidocaine dissociation is not (Table 5). Conversely, the dissociation of propranolol or lidocaine from albumin is markedly enhanced in the liver microcirculation.



Figure 8.

A: Percent extraction (ET) of inulin and three plasma proteins across the rat prostate gland microvasculature following a single arterial injection. Data are means ± SE (n = 3–7 rats per point). The ET values of albumin, transferrin, and inulin are comparable, whereas there is a marked increase (P < 0.05) of the prostatic extraction of testosterone‐binding globulin (TeBG). B: Darkfield micrograph of thaw‐mount autoradiogram of rat ventral prostate gland obtained 60 s after a descending aortic infusion of [3H]‐testosterone bound to the sex hormone–binding globulin (SHBG) in human pregnancy serum. These studies show rapid exodus of the [3H]‐testosterone–SHBG complex from prostatic microvessels and rapid distribution into the stromal compartment of the prostate gland. Conversely, when [3H]‐testosterone was infused in buffer without SHBG, the steroid molecule uniformly distributed over both the stromal and epithelial compartments. [From Ellison and Pardridge 55 and Sakiyama et al. 225 with permission.]



Figure 9.

A: Photomicrograph of isolated microvessels obtained from 28‐day‐old rabbit brain. These capillaries were used in radioreceptor assays to probe for the presence of plasma protein–specific receptors. B, left: Binding of [3H]‐testosterone‐binding globulin (TeBG) at 37°C to capillaries isolated from either 28‐day‐old (open circles) or adult (triangles) rabbits. Inclusion of 50% 28‐day‐old rabbit serum results in a marked diminution in the uptake of [3H]‐TeBG by capillaries isolated from 28‐day‐old rabbits. B, right: Uptake of [3H]‐albumin by capillaries isolated from 28‐day‐old rabbit brain is plotted vs. incubation time in the absence (closed circles) or presence (open circles) of a 50% dilution of 28‐day‐old rabbit serum. Residual uptake of [14C]‐sucrose, an extracellular fluid marker, is also shown. [From Pardridge et al. 176 with permission.]



Figure 10.

A: Steady‐state model of testosterone transport through the brain capillary wall and into brain cells. Pools of globulin‐bound, albumin‐bound, and free ligand in the systemic circulation are denoted as GL°, AL°, and LF°, respectively; pools of globulin‐bound, albumin‐bound, and plasma bioavailable hormone in the brain capillary are denoted as GL, AL, and LF, respectively. Pools of free and cytoplasmic bound steroid hormone in brain cells are denoted as LM and PL, respectively; t is mean capillary transit time in brain. B: Predicted steady‐state concentrations of testosterone in the various pools of the brain capillary and in brain cells. Pool sizes represent the basal state, which is simulation 1 in Table 9. The concentration of free cytosolic testosterone in brain cells is predicted to approximate the concentration of albumin‐bound hormone in the circulation but is more than tenfold greater than the concentration of free hormone measured in vitro by equilibrium dialysis. [From Pardridge and Landaw 180 with permission.]



Figure 11.

A: Steady‐state model of triiodothyronine transport in the liver microcirculation in vivo. Rate constants and hormone pools are defined in Table 10. B: The parameters in Table 10 were substituted into the steady‐state model equation using a program in BASIC to generate the predicted pool‐size concentrations shown in the figure, which correspond to simulation 1 of Table 11. GL°, AL°, and LF°: pools of globulin‐bound, albumin‐bound, and free ligand, respectively. GL, AL, and LF: pools of globulin‐bound, albumin‐bound, and plasma available hormone, respectively. LM and PL, pools of free and cytoplasmic bound thyroid hormone, respectively. [From Pardridge 173 and Pardridge and Landaw 181 with permission.]



Figure 12.

A: Fractions of free plus albumin‐bound testosterone and estradiol in vitro and bioavailable testosterone and estradiol in rat salivary gland in vivo are compared, showing that sex hormone–binding globulin (SHBG)‐bound estradiol, but not SHBG‐bound testosterone, is readily available for transport into rat salivary gland. In addition, albumin‐bound testosterone or estradiol is bioavailable in salivary gland capillaries. These in vivo measurements were made at 15 s after a single carotid artery injection of [3H]‐hormone mixed in human female serum. This short period is sufficient to allow for rapid distribution of hormone into the glandular epithelium, as shown by the autoradiographic studies in B. [From Pardridge 170 with permission.] B: Thaw‐mount autoradiogram of rat salivary gland removed 15 s after single carotid artery injection of [3H]‐estradiol dissolved in Ringer‐HEPES buffer containing 0.1 g/dl bovine albumin. The [3H]‐estradiol is found throughout the gland, with concentration over the salivary gland ductules. The tissue was counterstained after autoradiography with methylgreen‐pyronin. [From Cefalu et al. 28 with permission.] C: One‐dimensional thinlayer chromatographic separation of brain, cervical lymph node, and salivary gland homogenates of tissue obtained 60 s after a single carotid artery injection of [3H]‐testosterone (50 μCi/ml) in Ringer‐HEPES buffer containing 0.1 g/dl bovine albumin. Migration of testosterone or several other metabolites in the one‐dimensional system is shown. The minor peak in the brain and lymph node studies that co‐migrated with androstenedione (peak 2) represents an impurity in the isotope, as this was found also in the [3H]‐testosterone obtained from the manufacturer. The data show that while testosterone is rapidly metabolized in salivary gland, there is no significant metabolism in the whole brain or lymph node within 60 s after administration in vivo. [From Cefalu et al. 28 with permission.]



Figure 13.

Amino‐acid sequence of bovine serum albumin, displayed in a model showing the linking of cysteines to form multiple loops as proposed by Brown 22.



Figure 14.

Three‐dimensional structure of human serum albumin predicted from X‐ray diffraction studies. The amino (N) and carboxyl (C) termini are shown. The six different putative binding sites on the albumin molecule are shown, designated IA, IB, IIA, IIB, IIIA, and IIIB. The principal drug‐binding sites on albumin are IIA and IIIA. [From Carter and He 26 with permission.]



Figure 15.

Approximate amino‐acid residues comprising the six binding domains in serum albumin. [Drawn from data of Carter and He 26 with permission.]



Figure 16.

Unidirectional extraction of [125I]‐thyroxine (T4) into rat liver in vivo is shown for three types of portal vein injection vehicles: Ringer‐HEPES buffer plus 0.1 g/100 dl bovine albumin, normal human serum, or serum obtained from patients with familial dysalbuminemic hyperthyroxinemia (FDH) in the presence of 0 or 25 μM unlabeled T4, and rabbit anti‐T4 antiserum. Extraction of T4 following portal vein injection of Ringer‐HEPES buffer represents the situation when approximately 100% of T4 is available for extraction by hepatocytes; extraction of T4 by liver following portal vein injection of the isotope dissolved in the T4 antiserum represents the baseline extraction when the amount of injected T4 available for extraction by hepatocytes is essentially nil. Horizontal bars represent the mean ± one standard deviation for the extraction of T4 in either Ringer's solution or the T4 antiserum. [From Cefalu et al. 29 with permission.]



Figure 17.

Stereo view of the three‐dimensional structure predicted from X‐ray diffraction for the prealbumin homotetramer. [From Blake and Oatley 13 with permission.]



Figure 18.

A: Extraction of [125I]‐thryoxine (T4) into rat liver following portal vein injection of the isotope dissolved in three different solutions: Ringer‐HEPES buffer containing 0.1 g/dl bovine albumin (upper horizontal bar), control or thyroid hormone–binding globulin (TBG)–deficient human serum or normal rat serum (closed circles), T4‐specific rabbit antiserum (lower horizontal bar). Extractions obtained following injection of Ringer's solution or T4 antiserum represent the hepatocyte extraction when approximately 100% and 0%, respectively, of labeled hormone is available for transport into liver. Horizontal bars represent mean ± SE (n = 3–6 rats per point). The number of subjects in each category is shown in parentheses. B: Extraction of [125I]‐T4 by rat liver in vivo is plotted vs. the concentration of human prealbumin in the portal vein injection solution. Human prealbumin and [125I]‐T4 were mixed with either 5 or 0.1 g/dl bovine albumin or 5 g/dl dextran (65,000 daltons). Dashed line represents the extraction of T4 predicted on the basis of the bound T4 fraction as measured in vitro by equilibrium dialysis at each concentration of prealbumin. All concentrations of human prealbumin (0.01–0.3 mg/ml) bound more than 96% of T4 in vitro. Solid horizontal line represents hepatic extraction of T4 in the presence of a 10% T4 antiserum. [From Pardridge et al. 188 with permission.]



Figure 19.

Heterogeneity of thyroid hormone–binding globulin (TBG) structure and function Right: Extraction of [125I]‐thyroxine (T4) or [125I]‐triiodethyronine (T3) by rat liver is plotted vs. the type of serum added to the portal vein injection solution. Plasma‐free solutions contain 0.1 g/dl bovine albumin; T4‐, or T4‐specific antiserum solutions were diluted to 10%. All other samples were injected at 67% serum solutions. Each point represents a different patient, volunteer, or animal. Boxes represent the mean ± SD. Normal, human, and cord samples were obtained from both females and males. BCP, birth control pills. Left: Autoradiogram of [125I]‐T3 or [125I]‐T4 bound to TBG isoforms, albumin isoforms, and prealbumin in serum from normal male subjects, cirrhotic male patients, pregnant subjects, and normal female subjects following separation by isoelectric focusing. The pH values of the gel are shown in the ordinate of the figure. [From Pardridge 173 with permission.]



Figure 20.

A: Brain uptake index (BUI) for [3H]‐testosterone and [3H]‐estradiol relative to [14C]‐butanol is shown for five to nine patients in seven clinical conditions. Vertical rectangles are means ± SD; horizontal line is mean of testosterone or estradiol BUI in absence of plasma proteins. BCP, birth control pill–treated women; PMP, postmenopausal women. B: Reciprocal of BUI for [3H]‐testosterone (T) and [3H]‐estradiol (E2) is plotted vs. the level of sex hormone–binding globulin (SHBG) in human serum. Data for BUI are shown in A. P, pregnancy; B, birth control pills; T, thin postmenopausal female; F, normal follicular phase female; O, obese postmenopausal female; M, normal male; H, hirsute female. Data obtained by linear regression are shown in inset for both plots. [From Pardridge et al. 186 with permission.]



Figure 21.

In vitro free plus albumin‐bound, in vivo brain bioavailable, and in vivo liver bioavailable fractions for human male serum for three steroid hormones. [From Pardridge 171 with permission.]



Figure 22.

Metabolic clearance rate (MCR) and transport clearance rate (TCR) ratios for testosterone (T)/dihydrotestosterone (DHT) are compared for humans and rabbits. Human TCR ratio was measured in rat brain using human male serum. Rabbit TCR ratio was measured in rabbit uterus using rabbit serum 1. Human and rabbit MCR ratios were reported by Vermeulen and Andó 270 and Mahoudeau et al. 140, respectively. The T/DHT MCR ratio in the rhesus monkey 231 is virtually identical to the ratio for humans 270.



Figure 23.

A: Rat brain extraction of [3H]‐testosterone or [3H]‐estradiol after carotid arterial injection of labeled hormone mixed in either male cirrhotic or control human male serum. Rectangles represent means ± SD. The data show that unidirectional testosterone extraction by brain is decreased 33% (P < 0.0025) using cirrhotic serum, and this parallels a 2.6‐fold increase in sex hormon–binding globulin (SHBG) and a 40% decrease in serum albumin in cirrhosis. However, unidirectional clearance of estradiol by rat brain was not decreased using cirrhotic serum, despite the marked increase in SHBG, the decrease in albumin, and the 41% decrease in the non‐SHBG‐bound fraction of estradiol in cirrhosis. Brain bioavailable estradiol using cirrhotic serum, 54 ± 4%, exceeds non‐SHBG‐bound estradiol, 36 ± 6%, in cirrhotic serum, indicating that SHBG‐bound estradiol is available for transport into brain from plasma protein–bound pools in cirrhotic serum. Conversely, SHBG‐bound estradiol was not available for transport into brain when serum was obtained from other clinical groups (Fig. 20). [From Sakiyama et al. 224 with permission.]

B: Isoelectric focusing separation of [3H]‐testosterone‐and [3H]‐estradiol‐binding isoforms of SHBG in concanavalin‐A–glycoprotein fraction of a cirrhotic male serum pool and a normal male serum pool. The pH values of the gel are shown by a diagonal line in the bottom half of the figure. C: Profiles of estradiol‐ or testosterone‐binding isoforms of SHBG from B are replotted to allow direct comparison of results between normal male and cirrhotic male serum pools. The pH profile is shown by the diagonal line. [From Terasaki et al. 253 with permission.]



Figure 24.

A: Rat brain extraction of [3H]‐testosterone or [3H]‐estradiol after carotid arterial injection of labeled hormone mixed in either male cirrhotic or control human male serum. Rectangles represent means ± SD. The data show that unidirectional testosterone extraction by brain is decreased 33% (P < 0.0025) using cirrhotic serum, and this parallels a 2.6‐fold increase in sex hormon–binding globulin (SHBG) and a 40% decrease in serum albumin in cirrhosis. However, unidirectional clearance of estradiol by rat brain was not decreased using cirrhotic serum, despite the marked increase in SHBG, the decrease in albumin, and the 41% decrease in the non‐SHBG‐bound fraction of estradiol in cirrhosis. Brain bioavailable estradiol using cirrhotic serum, 54 ± 4%, exceeds non‐SHBG‐bound estradiol, 36 ± 6%, in cirrhotic serum, indicating that SHBG‐bound estradiol is available for transport into brain from plasma protein–bound pools in cirrhotic serum. Conversely, SHBG‐bound estradiol was not available for transport into brain when serum was obtained from other clinical groups (Fig. 20). [From Sakiyama et al. 224 with permission.]

B: Isoelectric focusing separation of [3H]‐testosterone‐and [3H]‐estradiol‐binding isoforms of SHBG in concanavalin‐A–glycoprotein fraction of a cirrhotic male serum pool and a normal male serum pool. The pH values of the gel are shown by a diagonal line in the bottom half of the figure. C: Profiles of estradiol‐ or testosterone‐binding isoforms of SHBG from B are replotted to allow direct comparison of results between normal male and cirrhotic male serum pools. The pH profile is shown by the diagonal line. [From Terasaki et al. 253 with permission.]

References
 1. Ain, K. B., Y. Mori, and S. Refetoff. Reduced clearance rate of thyroxine‐binding globulin (TBG) with increased sialylation: a mechanism for estrogen‐induced elevation of serum TBG concentration. J. Clin. Endocrinol. Metab. 65: 689–696, 1987.
 2. Ain, K. B., and S. Refetoff. Relationship of oligosaccharide modification to the cause of serum thyroxine‐binding globulin excess. J. Clin. Endocrinol. Metab. 66: 1037–1043, 1988.
 3. Alpert, E. Human alpha‐fetoprotein (AFP) developmental and biological characteristics. In: Prevention of Neural Tube Defects: The Role of Alpha Feto Protein, edited by B. F. Crandall and M. A. B. Brazier. New York: Academic, 1978, p. 19–26.
 4. Baird, D. T., R. Horton, C. Longcope, and J. F. Tait. Steroid dynamics under steady‐state conditions. Recent Prog. Horm. Res. 25: 611–664, 1969.
 5. Baker, K. J., and S. E. Bradley. Binding of sulfobromophthalein (BSP) sodium by plasma albumin. Its role in hepatic BSP extraction. J. Clin. Invest. 45: 281–287, 1966.
 6. Barlow, J. W., J. M. Csicsmann, E. L. White, J. W. Funder, and J. R. Stockigt. Familial euthyroid thyroxine excess: characterization of abnormal intermediate affinity thyroxine binding to albumin. J. Clin. Endocrinol. Metab. 55: 244–250, 1982.
 7. Barnhart, J. L., B. L. Witt, W. G. Hardison, and R. N. Berk. Uptake of iopanoic acid by isolated rat hepatocytes in primary culture. Am. J. Physiol. 244 (Gastrointest. Liver Physiol. 7): G630–G636, 1983.
 8. Bartlett, P. A., and C. K. Marlowe. Evaluation of intrinsic binding energy from a hydrogen bonding group in an enzyme inhibitor. Science 235: 569–571, 1987.
 9. Bass, L., P. Robinson, and A. J. Braken. Hepatic elimination of flowing substances: the distributed model. J. Theor. Biol. 72: 161–184, 1978.
 10. Bell, D. R., P. D. Watson, and E. M. Renkin. Exclusion of plasma proteins in interstitium of tissues from the dog hind paw. Am. J. Physiol. 239 (Heart Circ. Physiol. 10): H532–H538, 1980.
 11. Benveniste, H., J. Drejer, A. Schousboe, and N. H. Diemer. Regional cerebral glucose phosphorylation and blood flow after insertion of a microdialysis fiber through the dorsal hippocampus in the rat. J. Neurochem. 49: 729–734, 1987.
 12. Bernstein, G., and J. H. Oppenheimer. Factors influencing the concentration of free and total thyroxine in patients with nonthyroidal disease. J. Clin. Endocrinol. 26: 195–201, 1966.
 13. Blake, C. C. F., and S. J. Oatley. Protein‐DNA and protein‐hormone interactions in prealbumin: A model of the thyroid hormone nuclear receptor? Nature 268: 115–120, 1977.
 14. Blondeau, J.‐P., J. Osty, and J. Francon. Characterization of the thyroid hormone transport system of isolated hepatocytes. J. Biol. Chem. 263: 2685–2692, 1988.
 15. Bloomer, J. R., P. D. Berk, J. Vergalla, and N. I. Berlin. Influence of albumin on the hepatic uptake of unconjugated bilirubin. Clin. Sci. Mol. Med. 45: 505–516, 1973.
 16. Bolton, N. J., R. Lahtonen, G. L. Hammond, and R. Vihko. Distribution and concentrations of androgens in epithelial and stromal compartments of the human benign hypertrophic prostate. J. Endocrinol. 90: 125–131, 1981.
 17. Bonner, W. M. Protein migration into nuclei. 1. Frog oocyte nuclei in vivo accumulate microinjected histones, allow entry to small proteins, and exclude large proteins. J. Cell Biol. 64: 421–430, 1975.
 18. Bourget, C., C. Flood, and C. Longcope. Steroid dynamics in the rabbit. Steroids 43: 225–233, 1984.
 19. Brandes, R., R. K. Ockner, R. A. Weisiger, and N. Lysenko. Specific and saturable binding of albumin to rat adipocytes: modulation by epinephrine and possible role in free fatty acid transfer. Biochem. Biophys. Res. Commun. 105: 821–827, 1982.
 20. Brent, G. A., J. M. Hershman, A. W. Reed, A. Sastre, and J. Lieberman. Serum angiotensin‐converting enzyme in severe nonthyroidal illnesses associated with low serum thyroxine concentration. Ann. Intern. Med. 100: 680–683, 1984.
 21. Brightman, M. W. Morphology of blood‐brain interfaces. Exp. Eye Res. 25 (Suppl.): 1–25, 1977.
 22. Brown, J. R. Serum albumin: amino acid sequence. In: Albumin Structure, Function, and Uses, edited by V. M. Rosehoer, M. Oratz, and M. A. Rothschild. New York: Pergamon, 1977, p. 27–51.
 23. Brown, J. R., and P. Shockley. Serum albumin: structure and characterization of its ligand binding sites. In: Lipid‐Protein Interactions, edited by P. C. Jost and O. H. Griffith. New York: Wiley, 1982, vol. 1, p. 25–68.
 24. Brown‐Grant, K., R. D. Brennan, and F. E. Yates. Simulation of the thyroid hormone‐binding protein interactions in human plasma. J. Clin. Endocrinol. 30: 733–751, 1970.
 25. Burke, C. W., and D. C. Anderson. Sex‐hormone‐binding globulin is an oestrogen amplifier. Nature 240: 38–40, 1972.
 26. Carter, D. C., and J. X. He. Structure of serum albumin. Adv. Protein Chem. 45: 153–203, 1994.
 27. Cefalu, W. T., and W. M. Pardridge. Augmented transport and metabolism of sex steroids in lymphoid neoplasia in the rat. Endocrinology 120: 1000–1009, 1987.
 28. Cefalu, W. T., W. M. Pardridge, G. Chaudhuri, and H. L. Judd. Serum bioavailability and tissue metabolism of testosterone and estradiol in rat salivary gland. J. Clin. Endocrinol. Metab. 63: 20–28, 1986.
 29. Cefalu, W. T., W. M. Pardridge, and B. N. Premachandra. Hepatic bioavailability of thyroxine and testosterone in familial dysalbuminemic hyperthyroxinemia. J. Clin. Endocrinol. Metab. 61: 783–786, 1985.
 30. Chambers, R., and B. W. Zweifach. Intercellular cement and capillary permeability. Physiol. Rev. 27: 436–163, 1947.
 31. Chaudhuri, G., K. A. Steingold, W. M. Pardridge, and H. L. Judd. TeBG‐ and CBG‐bound steroid hormones in rabbits are available for influx into uterus in vivo. Am. J. Physiol. 254 (Endocrinol. Metab. 17): E79–E83, 1988.
 32. Chaudhuri, G., C. Verheugen, W. M. Pardridge, and H. L. Judd. Selective availability of protein bound estrogen and estrogen conjugates to the rat kidney. J. Endocrinol. Invest. 10: 283–290, 1987.
 33. Chopra, I. J., J. M. Hershman, W. M. Pardridge, and J. T. Nicoloff. Thyroid function in nonthyroidal illnesses. Ann. Intern. Med. 98: 946–957, 1983.
 34. Christensen, H. N. Some special kinetic problems of transport. Adv. Enzymol. 32: 1–20, 1969.
 35. Cooke, N. E., and E. V. David. Serum vitamin D‐binding protein is a third member of the albumin and alpha fetoprotein gene family. J. Clin. Invest. 76: 2420–2424, 1985.
 36. Cornford, E. M., L. D. Braun, W. M. Pardridge, and W.H. Oldendorf. Determination of blood flow rate and cellular influx of glucose and arginine in mouse liver in vivo. Am. J. Physiol. 238 (Heart Circ. Physiol. 9): H553–H560, 1980.
 37. Corvol, P., and C. W. Bardin. Species distribution of testosterone‐binding globulin. Biol. Reprod. 8: 277–282, 1973.
 38. Cowan, R. A., S. K. Cowan, C. A. Giles, and J. K. Grant. Prostatic distribution of sex hormone‐binding globulin and cortisol‐binding globulin in benign hyperplasia. J. Endocrinol. 71: 121–131, 1976.
 39. Crone, C. Permeability of capillaries in various organs as determined by use of the “indicator diffusion” method. Acta Physiol. Scand. 58: 292–305, 1973.
 40. Crone, C., and D. G. Levitt. Capillary permeability to small solutes. In: Handbook of Physiology: The Cardiovascular System. Microcirculation, edited by E. M. Renkin and C. C. Michel. Bethesda, MD: Am. Physiol. Soc., 1984, sect. 2, vol IV, chapt. 10, p. 411–466.
 41. Daniel, J.‐Y., F. Leboulenger, H. Vaudry, H. H. Floch, and I. Assenmacher. Interrelations between binding affinity and metabolic clearance rate for the main corticosteroids in the rabbit. J. Steroid Biochem. 16: 379–384, 1982.
 42. Desjardins, C., and B. R. Duling. Microvessel hematocrit: measurement and implications for capillary oxygen transport. Am. J. Physiol. 252 (Heart Circ. Physiol. 21): H494–H503, 1987.
 43. Dewey, W. C. Vascular‐extravascular exchange of I131 plasma proteins in the rat. Am. J. Physiol. 197: 423–431, 1959.
 44. Diamond, J. M., and E. M. Wright. Molecular forces governing non‐electrolyte permeation through cell membranes. Proc. R. Soc. Lond. B Biol. Sci. 172: 276–316, 1969.
 45. Dickson, P. W., G. J. Howlett, and G. Schreiber. Rat transthyretin (prealbumin). J. Biol. Chem. 260: 8214–8219, 1985.
 46. Drinker, C. K. The permeability and diameter of the capillaries in the web of the brown frog (Rana temporaria) when perfused with solutions containing pituitary extract and horse serum. J. Physiol. (Lond.) 63: 249–269, 1927.
 47. Dubey, R. K., C. B. McAllister, M. Inoue, and G. R. Wilkinson. Plasma binding and transport of diazepam across the blood‐brain barrier. No evidence for in vivo enhanced dissociation. J. Clin. Invest. 84: 1155–1159, 1989.
 48. Dueland, S., R. Bouillon, H. van Baelen, J. I. Pederson, P. Helgerud, and C. A. Drevon. Binding protein for vitamin D and its metabolites in rat mesenteric lymph. Am. J. Physiol. 249 (Endocrinol. Metab. 20): E1–E5, 1985.
 49. Dunn, J. F., B. C. Nisula, and D. Rodbard. Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone‐binding globulin and corticosteroid‐binding globulin in human plasma. J. Clin. Endocrinol. Metab. 53: 58–68, 1981.
 50. Dykstra, K. H., J. K. Hsiao, P. F. Morrison, P.M. Bungay, I. N. Mefford, M. M. Scully, and R. L. Dedrick. Quantitative examination of tissue concentration profiles associated with microdialysis. J. Neurochem. 58: 931–940, 1992.
 51. Eckel, J., G. S. Rao, M. L. Rao, and H. Breuer. Uptake of L‐triiodothyronine by isolated rat liver cells. Biochem J. 182: 473–491, 1979.
 52. Ekins, R. P. Methods for the measurement of free thyroid hormones. In: Free Thyroid Hormones, edited by R. Ekins, G. Faglia, F. Pennisi, and A. Pinchera. Amsterdam: Excerpta Medica, 1979, p. 72.
 53. Ekins, R. P., and P. R. Edwards. Plasma protein‐mediated transport of steroid and thyroid hormones: a critique. Am. J. Physiol. 255 (Endocrinol. Metab. 18): E403–E409, 1988.
 54. Ellison, S. A., and W. M. Pardridge. Reduction of testosterone availability to 5α‐reductase by human sex hormone‐binding globulin in the rat ventral prostate gland in vivo. Prostate 17: 281–291, 1990.
 55. Endo, T., M. Eilers, and G. Schatz. Binding of a tightly folded artificial mitochondrial precursor protein to the mitochondrial outer membrane involves a lipid‐mediated conformational change. J. Biol. Chem. 264: 2951–2956, 1989.
 56. Evans, J. J. Progesterone in saliva does not parallel unbound progesterone in plasma. Clin. Chem. 32: 542–544, 1986.
 57. Faber, J., O. Faber, A. Wennlund, and J. Wahren. Splanchnic extraction of 3,3′‐diiodothyronine and 3′,5′‐diiodothyronine in hyperthyroidism. J. Clin. Endocrinol. Metab. 59: 147–150, 1984.
 58. Farrell, C. L., J. Yang, and W. M. Pardridge. GLUT‐1 glucose transporter is present within apical and basolateral membranes of brain epithelial interfaces and in microvascular endothelia with and without tight junctions. J. Histochem. Cytochem. 40: 193–199, 1992.
 59. Feng, L., C. Z. Hu, and J. D. Andrade. Scanning tunneling microscopic images of adsorbed serum albumin on highly oriented pyrolytic graphite. J. Colloid Interface Sci. 126: 650–653, 1988.
 60. Fleischer, A. B., W. O. Shurmantine, B. A. Luxon, and E. L. Forker. Palmitate uptake by hepatocyte monolayers. J. Clin. Invest. 77: 964–970, 1986.
 61. Flink, I. L., T. J. Bailey, T. A. Gustafson, B. E. Markham, and E. Morkin. Complete amino acid sequence of human thyroxine‐binding globulin deduced from cloned DNA: close homology to the serine antiproteases. Proc. Natl. Acad. Sci. U.S.A. 83: 7708–7712, 1986.
 62. Forker, E. L., and B. Luxon. Hepatic transport kinetics and plasma disappearance curves: distributed modeling versus conventional approach. Am. J. Physiol. 235 (Endocrinol. Metab. Gastrointest. Physiol. 4): E648–E660, 1978.
 63. Forker, E. L., and B. A. Luxon. Albumin helps mediate removal of taurocholate by rat liver. J. Clin. Invest. 67: 1517–1522, 1981.
 64. Forker, E. L., and B. A. Luxon. Albumin‐mediated transport of rose bengal by perfused rat liver. J. Clin. Invest. 72: 1764–1771, 1983.
 65. Forker, E. L., and B. A. Luxon. Effects of unstirred Disse fluid, nonequilibrium binding, and surface‐mediated dissociation on hepatic removal of albumin‐bound organic anions. Am. J. Physiol. 248 (Gastrointest. Liver Physiol. 11): G709–G717, 1985.
 66. Forker, E. L., B. A. Luxon, and V. S. Sharma. Hepatic transport and binding of rose bengal in the presence of albumin and gamma globulin. Am. J. Physiol. 248 (Gastrointest. Liver Physiol. 11): G702–G708, 1985.
 67. Forker, E. L., B. A. Luxon, M. Snell, and W. O. Shurmantine. Effect of albumin binding on the hepatic transport of rose bengal: surface‐mediated dissociation of limited capacity. J. Pharmacol. Exp. Ther. 223: 342–347, 1982.
 68. Frairia, R., N. Fortunati, F. Fissore, A. Fazzari, P. Zeppegno, L. Varvello, M. Orsello, and L. Berta. The membrane receptor for sex steroid binding protein is not ubiquitous. J. Endocrinol. Invest. 15: 617–620, 1992.
 69. Ganguly, M., R. H. Carnighan, and U. Westphal. Steroid‐protein interactions. XIV. Interaction between human α1‐acid glycoprotein and progesterone. Biochemistry 6: 2803–2814, 1967.
 70. Gärtner, R., K. Horn, C. R. Pickardt, and P. C. Scriba Thyroxine‐binding globulin: investigation of microheter‐ogeneity. J. Clin. Endocrinol. Metab. 52: 657–664, 1981.
 71. Gillette, J. R. Overview of drug‐protein binding. Ann. N. Y. Acad. Sci. 226: 6–17, 1973.
 72. Giorgi, E. P., and W. D. Stein. The transport of steroids into animal cells in culture. Endocrinology 108: 688–697, 1981.
 73. Goldman, M., M. B. Dratman, F. L. Crutchfield, A. S. Jennings, J. A. Maruniak, and R. Gibbons. Intrathecal triiodothyronine administration causes greater heart rate stimulation in hypothyroid rats than intravenously delivered hormone. J. Clin. Invest. 76: 1622–1625, 1985.
 74. Goodman, D. S. Vitamin A and retinoids in health and disease. N. Engl. J. Med. 310: 1023–1031, 1984.
 75. Gordon, G. G., J. Olivo, F. Fafil, and A. L. Southren. Conversion of androgens to estrogens in cirrhosis of the liver. J. Clin. Endocrinol. Metab. 40: 1018–1026, 1975.
 76. Goresky, C. A., D. S. Daly, S. Mishkin, and I. M. Arias. Uptake of labeled palmitate by the intact liver: role of intracellular binding sites. Am. J. Physiol. 234 (Endocrinol. Metab. Gastrointest. Physiol. 3): E542–E553, 1978.
 77. Griffin, P. R., S. Kumar, J. Shabanowitz, H. Charbonneau, P. C. Namkung, K. A. Walsh, D. F. Hunt, and P. H. Petra. The amino acid sequence of the sex steroid‐binding protein of rabbit serum. J. Biol. Chem. 264: 19066–19075, 1989.
 78. Gumucio, J. J. Functional and anatomic heterogeneity in the liver acinus: impact on transport. Am. J. Physiol. 244 (Gastrointest. Liver Physiol. 7): G578–G582, 1983.
 79. Hagen, G. A., and L. A. Solberg, Jr. Brain and cerebrospinal fluid permeability to intravenous thyroid hormones. Endocrinology 95: 1398–1410, 1974.
 80. Hammond, G. L. Molecular properties of corticosteroid binding globulin and the sex‐steroid binding proteins. Endocr. Rev. 11: 65–79, 1990.
 81. Hammond, G. L., and W. P. Bocchinfuso. Sex hormone‐binding globulin/androgen‐binding protein: steroid‐binding and dimerization domains. J. Steroid Biochem. Mol. Biol. 53: 543–552, 1995.
 82. Hammond, G. L., C. L. Smith, I. S. Goping, D. A. Underhill, M. J. Harley, J. Reventos, N. A. Musto, G. L. Gunsalus, and C. W. Bardin. Primary structure of human corticosteroid binding globulin, deduced from hepatic and pulmonary cDNAs, exhibits homology with serine protease inhibitors. Proc. Natl. Acad. Sci. U.S.A. 84: 5153–5157, 1987.
 83. Hammond, G. L., C. L. Smith, N. A. M. Paterson, and W. J. Sibbald. A role for corticosteroid‐binding globulin in delivery of cortisol to activated neutrophils. J. Clin. Endocrinol. Metab. 71: 34–39, 1990.
 84. Hammond, G. L., D. A. Underhill, C. L. Smith, I. S. Goping, M. J. Harley, N. A. Musto, C. Y. Cheng, and C. W. Bardin. The cDNA‐deduced primary structure of human sex hormone‐binding globulin and location of its steroid‐binding domain. FEBS Lett. 215: 100–104, 1987.
 85. Haraldsson, B. Physiological studies of macromolecular transport across capillary walls. Acta Physiol. Scand. Suppl. 553: 1–40, 1986.
 86. Hayashi, Y., Y. Mori, O. E. Janssen, T. Sunthornthepvarakul, R. E. Weiss, K. Takeda, M. Weinberg, H. Seo, G. I. Bell, and S. Refetoff. Human thyroxine‐binding globulin gene: complete sequence and transcriptional regulation. Mol. Endocrinol. 7: 1049–1060, 1993.
 87. He, X. M., and D. C. Carter. Atomic structure and chemistry of human serum albumin. Nature 358: 209–215, 1992.
 88. Hervé, F., M.‐T. Martin, K. Rajkowski, P. Dessen, and N. Cittanova. Participation of the lone tryptophan residue of rat α‐foetoprotein in its drug‐binding sites. Biochem. J. 244: 81–85, 1987.
 89. Heyns, W., and P. De Moor Kinetics of dissociation of 17β3‐hydroxysteroids from the steroid binding β‐globulin of human plasma. J. Clin. Endocrinol. 32: 147–154, 1971.
 90. Hillier, A. P. The release of thyroxine from serum protein in the vessels of the liver. J. Physiol. (Lond.) 203: 419–434, 1969.
 91. Hillier, A. P. The rate of triiodothyronine dissociation from binding sites in human plasma. Acta Endocrinol. 80: 49–57, 1975.
 92. Hillier, A. P., and W. E. Balfour. Human thyroxine‐binding globulin and thyroxine‐binding pre‐albumin: dissociation rates. J. Physiol. (Lond.) 217: 625–634, 1971.
 93. Honig, C. R., and C. L. Odoroff. Calculated dispersion of capillary transit times: significance for oxygen exchange. Am. J. Physiol. 240 (Heart Circ. Physiol. 11): H199–H208, 1981.
 94. Honig, C. R., C. L. Odoroff, and J. L. Frierson. Capillary recruitment in exercise: rate, extent, uniformity, and relation to blood flow. Am. J. Physiol. 238 (Heart Circ. Physiol. 9): H31–H42, 1980.
 95. Horie, T., T. Mizuma, S. Kasai, and S. Awazu. Conformational change in plasma albumin due to interaction with isolated rat hepatocyte. Am. J. Physiol. 254 (Gastrointest. Liver Physiol. 17): G465–G470, 1988.
 96. Horowitz, S. B. The permeability of the amphibian oocyte nucleus, in situ. J. Cell Biol. 54: 609–625, 1972.
 97. Hsiao, J. K., B. A. Ball, P. F. Morrison, I. N. Mefford, and P. M. Bungay. Effects of different semipermeable membranes on in vitro and in vivo performance of microdialysis probes. J. Neurochem. 54: 1449–1452, 1990.
 98. Ichikawa, M., S. C. Tsao, T.‐H. Lin, S. Miyauchi, Y. Sawada, T. Iga, M. Hanano, and Y. Sugiyama. “Albumin‐mediated transport phenomenon” observed for ligands with high membrane permeability. J. Hepatol. 16: 38–49, 1992.
 99. Inoue, M. Metabolism and transport of amphipathic molecules in analbuminemic rats and human subjects. Hepatology 5: 892–898, 1985.
 100. Inoue, M., H. Koyama, S. Nagase, and Y. Morino. Renal secretion of phenolsulfonphthalein: analysis of its vectorial transport in normal and mutant analbuminemic rats. J. Lab. Clin. Med. 105: 484–488, 1985.
 101. Inoue, M., K. Okajima, K. Itoh, Y. Ando, N. Watanabe, T. Yasaka, S. Nagase, and Y. Morino. Mechanism of furosemide resistance in analbuminemic rats and hypoalbuminemic patients. Kidney Int. 32: 198–203, 1987.
 102. Ishise, S., B. L. Pegram, J. Yamamoto, Y. Kitamura, and E. D. Frohlich. Reference sample microsphere method: cardiac output and blood flows in conscious rat. Am. J. Physiol. 239 (Heart Circ. Physiol. 10): H443–H449, 1980.
 103. Ivanov, K. P., M. K. Kalinina, and Y. I. Levkovich. Blood flow velocity in capillaries of brain and muscles and its physiological significance. Microvasc. Res. 22: 143–155, 1981.
 104. Ivanov, K. P., M. K. Kalinina, and Y. I. Levkovich. Microcirculation velocity changes under hypoxia in brain, muscles, liver, and their physiological significance. Microvasc. Res. 30: 10–18, 1985.
 105. Janin, J., and C. Chothia. The structure of protein‐protein recognition sites. J. Biol. Chem. 265: 16027–16030, 1990.
 106. Jones, D. R., S. D. Hall, E. K. Jackson, R. A. Branch, and G. R. Wilkinson. Brain uptake of benzodiazepines: effects of lipophilicity and plasma protein binding. J. Pharmacol. Exp. Ther. 245: 816–822, 1988.
 107. Joseph, D. R. Structure, function, and regulation of androgen‐binding protein/sex hormone‐binding globulin. Vitam. Horm. 49: 197–280, 1994.
 108. Joseph, D. R., S. H. Hall, and F. S. French. Rat androgen‐binding protein: evidence for identical subunits and amino acid sequence homology with human sex hormone‐binding globulin. Proc. Natl. Acad. Sci. U.S.A. 84: 339–343, 1987.
 109. Kambe, F., H. Seo, Y. Murata, and N. Matsui. Cloning of a complementary deoxyribonucleic acid coding for human thyroxine‐binding globulin (TBG): existence of two TBG messenger ribonucleic acid species possessing different 3′‐untranslated regions. Mol. Endocrinol. 2: 181–185, 1988.
 110. Kaptein, E. M., D. A. Grieb, C. A. Spencer, W. S. Wheeler, and J. T. Nicoloff. Thyroxine metabolism in the low thyroxine state of critical nonthyroidal illnesses. J. Clin. Endocrinol. Metab. 53: 764–771, 1981.
 111. Karplus, M., and J. A. McCammon. The dynamics of proteins. Sci. Am. 254: 42–51, 1986.
 112. Keller, N., U. I. Richardson, and F. E. Yates. Protein binding and the biological activity of corticosteroids: in vivo induction of hepatic and pancreatic alanine aminotransferases by corticosteroids in normal and estrogen‐treated rats. Endocrinology 84: 49–62, 1969.
 113. Kern, D. F., D. Levitt, and D. Wangensteen. Endothelial albumin permeability measured with a new technique in perfused rabbit lung. Am. J. Physiol. 245 (Heart Circ. Physiol. 16): H229–H236, 1983.
 114. Ketterer, B., T. Carne, and E. Tipping. Ligandin and protein A: intracellular binding proteins. In: Transport by Proteins, edited by G. I. Blauer and H. Sund. New York: de Gruyter, 1978, p. 79–92.
 115. Kety, S. S. The theory and applications of the exchange of inert gas at the lungs and tissues. Pharmacol. Rev. 3: 1–41, 1951.
 116. Kilvik, K., K. Furu, E. Haug, and K. M. Gautvik. The mechanism of 17β‐estradiol uptake into prolactin‐producing rat pituitary cells (GH3 cells) in culture. Endocrinology 117: 967–975, 1985.
 117. Klitzman, B., and B. R. Duling. Microvascular hematocrit and red cell flow in resting and contracting striated muscle. Am. J. Physiol. 237 (Heart Circ. Physiol. 8): H481–H490, 1979.
 118. Koshland, D. E., Jr. The Enzymes, edited by P. D. Boyer, H. Lardy, and K. Myrbäck. New York: Academic, 1959, vol. 1, p. 305.
 119. Kragh‐Hansen, U. Molecular aspects of ligand binding to serum albumin. Pharmacol. Rev. 33: 17–53, 1981.
 120. Krupenko, S. A., O. I. Kolesnik, N.I. Krupenko, and O. A. Strel'chyonok. Organization of the transcortin‐binding domain on placental plasma membranes. Biochim. Biophys. Acta 1235: 387–394, 1995.
 121. Krupenko, S. A., N. I. Krupenko, and B. J. Danzo. Interaction of sex hormone‐binding globulin in plasma membranes from the rat epididymis and other tissues. J. Steroid Biochem. Mol. Biol. 51: 115–124, 1994.
 122. Landis, E. M., and J. R. Pappenheimer. Exchange of substances through the capillary walls. In: Handbook of Physiology: Circulation. edited by W. F. Hamilton Washington D.C.: Am. Physiol. Soc., 1963, sect. 2, vol II, chapt. 29, p. 961–1034.
 123. Larson, K. B., J. Markham, and M. E. Raichle. Tracer‐kinetic models for measuring cerebral blood flow using externally detected radiotracers. J. Cereb. Blood Flow Metab. 7: 443–463, 1987.
 124. Lassen, N. A., and W. Perl. Tracer Kinetic Methods in Medical Physiology. New York: Raven, 1979, p. 1–189.
 125. Laufer, L. R., J. C. Gambone, G. Chaudhuri, W. M. Pardridge, and H. L. Judd. The effect of membrane permeability and binding by human serum proteins on sex steroid influx into the uterus. J. Clin. Endocrinol. Metab. 56: 1282–1287, 1983.
 126. Lee, J. Y., and M. Hirose. Partially folded state of the disulfide‐reduced form of human serum albumin as an intermediate for reversible denaturation. J. Biol. Chem. 267: 14753–14758, 1992.
 127. Lester, R., P. K. Eagon, and D. H. van Thiel Feminization of the alcoholic: the estrogen/testosterone ratio (E/T). Gastroenterology 76: 415–417, 1979.
 128. Lichenstein, H. S., D. E. Lyons, M. M. Wurfel, D. A. Johnson, M. D. McGinley, J. C. Leidli, D. B. Trollinger, J. P. Mayer, S. D. Wright, and M. M. Zukowski. Afamin is a new member of the albumin, α‐fetoprotein, and vitamin D‐binding protein gene family. J. Biol. Chem. 269: 18149–18154, 1994.
 129. Lin, T.‐H., and J. H. Lin. Effects of protein binding and experimental disease states on brain uptake of benzodiazepines in rats. J. Pharmacol. Exp. Ther. 253: 45–50, 1990.
 130. Lin, T.‐H., Y. Sawada, Y. Sugiyama, T. Iga, and M. Hanano. Effects of albumin and α1‐acid glycoprotein on the transport of imipramine and desipramine through the blood‐brain barrier in rats. Chem. Pharm. Bull. (Tokyo) 35: 294–301, 1987.
 131. Lin, T. H., Y. Sugiyama, Y. Sawada, T. Iga, and M. Hanano. Dialyzable serum cofactor(s) required for the protein‐mediated transport of DL‐propranolol into rat brain. Biochem. Pharmacol. 37: 2957–2961, 1988.
 132. Lin, T.‐H., Y. Sugiyama, Y. Sawada, S. Kawasaki, T. Iga, and M. Hanano. Effect of serum from renal failure and cirrhotic patients on the blood‐brain barrier permeability to DL‐propranolol in rats. Drug Metab. Dispos. Biol. Fate Chem. 16: 290–295, 1988.
 133. Listowsky, I., Z. Gatmaitan, and I. M. Arias. Ligandin retains and albumin loses bilirubin binding capacity in liver cytosol. Proc. Natl. Acad. Sci. U.S.A. 75: 1213–1216, 1978.
 134. Longcope, C., R. B. Billiar, Y. Takaoka, S. P. Reddy, D. Hess, and B. Little. Tissue metabolism of estrogens in the female rhesus monkey. Endocrinology 109: 392–396, 1981.
 135. Lovell‐Smith, C. J., and P. Garcia‐Webb. Glucocorticoids and the isolated rat hepatocyte. Biochem. Biophys. Res. Commun. 135: 160–165, 1986.
 136. Luft, A. J., and F. L. Lorscheider. Structural analysis of human and bovine α‐fetoprotein by electron microscopy, image processing, and circular dichroism. Biochemistry 22: 5978–5981, 1983.
 137. Luxon, B. A., P. D. King, and E. L. Forker. Only free bile acid drives ileal absorption of taurocholate. Am. J. Physiol. 250 (Gastrointest. Liver Physiol. 13): G648–G652, 1986.
 138. Maberly, G. F., K. V. Waite, A. E. Cutten, H. C. Smith, and C. J. Eastman. A reappraisal of the binding characteristics of human thyroxine‐binding globulin for 3,5,3′‐triiodothyronine and thyroxine. J. Clin. Endocrinol. Metab. 60: 42–47, 1985.
 139. Mahoudeau, J. A., P. Corvol, and H. Bricaire. Rabbit testosterone‐binding globulin. II. Effect on androgen metabolism in vivo. Endocrinology 92: 1120–1125, 1973.
 140. Mangel, W. F., B. Lin, and V. Ramakrishnan. Characterization of an extremely large, ligand‐induced conformational change in plasminogen. Science 248: 69–73, 1990.
 141. Martin, M. E., C. Benassayag, and E. A. Nunez. Selective changes in binding and immunological properties of human corticosteroid binding globulin by free fatty acids. Endocrinology 123: 1178–1186, 1988.
 142. Mendel, C. M., R. R. Cavalieri, and R. A. Weisiger. On plasma protein‐mediated transport of steroid and thyroid hormones. Am. J. Physiol. 255 (Endocrinol. Metab. 18): E221–E227, 1988.
 143. Mendel, C. M., R. R. Cavalieri, and R. A. Weisiger. Uptake of thyroxine by the perfused rat liver: implications for the free hormone hypothesis. Am. J. Physiol. 255 (Endocrinol. Metab. 18): E110–E119, 1988.
 144. Mendel, C. M., R. R. Cavalieri, L. A. Gavin, T. Pettersson, and M. Inoue. Thyroxine transport and distribution in Nagase analbuminemic rats. J. Clin. Invest. 83: 143–148, 1989.
 145. Mendel, C. M., R. W. Kuhn, R. A. Weisiger, R. R. Cavalieri, P. K. Siiteri, G. R. Cunha, and J. T. Murai. Uptake of cortisol by the perfused rat liver: validity of the free hormone hypothesis applied to cortisol. Endocrinology 124: 468–476, 1989.
 146. Mendel, C. M., R. A. Weisiger, and R. R. Cavalieri. Uptake of 3,5,3′‐triiodothyronine by the perfused rat liver: return to the free hormone hypothesis. Endocrinology 123: 1817–1824, 1988.
 147. Mercier, C., A. Alfsel, and E. E. Baulieu. Testosterone binding globulin in human plasma. In: Proc. 2nd Symp. Steroid Hormones, Ghent, 1965. New York: Excerpta Med., 1965, p. 212. (Int. Congr. Ser. 101.).
 148. Michel, C. C. Capillary permeability and how it may change. J. Physiol. 404: 1–29, 1988.
 149. Michel, C. C., M. E. Phillips, and M.R. Turner. The effects of native and modified bovine serum albumin on the permeability of frog mesenteric capillaries. J. Physiol. (Lond.) 360: 333–346, 1985.
 150. Mooradian, A. D., H. L. Schwartz, C. N. Mariash, and J. H. Oppenheimer. Transcellular and transnuclear transport of 3,5,3′‐triiodothyronine in isolated hepatocytes. Endocrinology 117: 2449–2456, 1985.
 151. Moresco, R. M., R. Casati, G. Lucignani, A. Carpinelli, K. Schmidt, S. Todde, F. Colombo, and F. Fazio. Systemic and cerebral kinetics of 16α[18F]fluoro‐17β‐estradiol: a ligand for the in vivo assessment of estrogen receptor binding parameters. J. Cereb. Blood Flow Metab. 15: 301–311, 1995.
 152. Müller, R. E., and H. H. Wotiz. Kinetics of estradiol entry into uterine cells. Endocrinology 105: 1107–1114, 1979.
 153. Nahon, J.‐L., I. Tratner, A. Poliard, F. Presse, M. Poiret, A. Gal, and J. M. Sala‐Trepat. Albumin and α‐fetoprotein gene expression in various nonhepatic rat tissues. J. Biol. Chem. 263: 11436–11442, 1988.
 154. Navab, M., J. E. Smith, and D. S. Goodman. Rat plasma prealbumin. J. Biol. Chem. 252: 5107–5114, 1977.
 155. Noé, G., Y. C. Cheng, M. Dabiké, and H. B. Croxatto. Tissue uptake of human sex hormone–binding globulin and its influence on ligand kinetics in the adult female rat. Biol. Reprod. 47: 970–976, 1992.
 156. Oldendorf, W. H. Measurement of brain uptake of radiolabeled substances using a tritiated water internal standard. Brain Res. 24: 372–376, 1970.
 157. Olivo, J., G. G. Gordon, F. Rafii, and A. L. Southren. Estrogen metabolism in hyperthyroidism and in cirrhosis of the liver. Steroids 26: 47–56, 1975.
 158. O'Neill, R. D., J.‐L. Gonzalez‐Mora, M. G. Boutelle, D. E. Ormonde, J. P. Lowry, A. Duff, B. Fumero, M. Fillenz, and M. Mas. Anomalously high concentrations of brain extracellular uric acid detected with chronically implanted probes: implications for in vivo sampling techniques. J. Neurochem. 57: 22–29, 1991.
 159. Oppenheimer, J. H. Thyroid hormone action at the nuclear level. Ann. Intern. Med. 102: 374–384, 1985.
 160. Oppenheimer, J. H., G. Bernstein, and J. Hasen. Estimation of rapidly exchangeable cellular thyroxine from the plasma disappearance curves of simultaneously administered thyroxine‐131I and albumin‐125I. J. Clin. Invest. 46: 762–777, 1967.
 161. Oppenheimer, J. H., and H. L. Schwartz. Stereospecific transport of triiodothyronine from plasma to cytosol and from cytosol to nucleus in rat liver, kidney, brain, and heart. J. Clin. Invest. 75: 147–154, 1985.
 162. Oppenheimer, J. H., M. I. Surks, and H. L. Schwartz. The metabolic significance of exchangeable cellular thyroxine. Recent. Prog. Horm. Res. 25: 381–422, 1969.
 163. Owens, S. M., M. Mayersohn, and J. R. Woodworth. Phencyclidine blood protein binding: influence of protein, pH, and species. J. Pharmacol. Exp. Ther. 226: 656–660, 1983.
 164. Paine, P. L. Nucleocytoplasmic movement of fluorescent tracers microinjected into living salivary gland cells. J. Cell Biol. 66: 652–657, 1975.
 165. Pang, K. S., and M. Rowland. Hepatic clearance of drugs. I. Theoretical considerations of a “well‐stirred” model and a “parallel‐tube” model. Influence of hepatic blood flow, plasma and blood cell binding, an hepatocellular enzymatic activity on hepatic drug clearance. J. Pharmacokinet. Biopharm. 5: 625–653, 1977.
 166. Pardridge, W. M. Carrier‐mediated transport of thyroid hormones through the rat blood–brain barrier: primary role of albumin‐bound hormone. Endocrinology 105: 605–612, 1979.
 167. Pardridge, W. M. Transport of protein‐bound hormones into tissues in vivo. Endocr. Rev. 2: 103–123, 1981.
 168. Pardridge, W. M. Brain metabolism: a perspective from the blood–brain barrier. Physiol. Rev. 63: 1481–1535, 1983.
 169. Pardridge, W. M. Plasma protein–mediated transport of steroid and thyroid hormones. Am. J. Physiol. 252 (Endocrinol. Metab. 15): E157–E164, 1987.
 170. Pardridge, W. M. Selective delivery of sex steroid hormones to tissues by albumin and by sex hormone–binding globulin. Oxf. Rev. Reprod. Biol. 10: 238–292, 1988.
 171. Pardridge, W. M. Hirsutism: free and bound testosterone [Reply]. Ann. Clin. Biochem. 27: 93–94, 1990.
 172. Pardridge, W. M. Transport of thyroid hormones into tissues in vivo. In: Thyroid Hormone Metabolism: Regulation and Clinical Implications, edited by S.‐Y. Wu Boston: Blackwell, 1991, p. 123–143.
 173. Pardridge, W. M., J. Eisenberg, and W. T. Cefalu. Absence of albumin receptor on brain capillaries in vivo or in vitro. Am. J. Physiol. 249 (Endocrinol. Metab. 12): E264–267, 1985.
 174. Pardridge, W. M., J. Eisenberg, G. Fierer, and R. W. Kuhn. CBG does not restrict blood–brain barrier corticosterone transport in rabbits. Am. J. Physiol. 251 (Endocrinol. Metab. 14): E204–E208, 1986.
 175. Pardridge, W. M., J. Eisenberg, G. Fierer, and N. A. Musto. Developmental changes in brain and serum binding of testosterone and in brain capillary uptake of testosterone‐binding serum proteins in the rabbit. Dev. Brain Res. 38: 245–253, 1988.
 176. Pardridge, W. M., and G. Fierer. Transport of tryptophan into brain from the circulating, albumin‐bound pool in rats and in rabbits. J. Neurochem. 54: 971–976, 1990.
 177. Pardridge, W. M., R. A. Gorski, B. M. Lippe, and R. Green. Androgens and sexual behavior. Ann. Intern. Med. 96: 488–501, 1982.
 178. Pardridge, W. M., and E. M. Landaw. Tracer kinetic model of blood–brain barrier transport of plasma protein–bound ligands. J. Clin. Invest. 74: 745–752, 1984.
 179. Pardridge, W. M., and E. M. Landaw. Testosterone transport in brain: primary role of plasma protein–bound hormone. Am. J. Physiol. 249 (Endocrinol. Metab. 12): E534–E542, 1985.
 180. Pardridge, W. M., and E. M. Landaw. Steady state model of 3,5,3′‐triiodothyronine transport in liver predicts high cellular exchangeable hormone concentration relative to in vitro free hormone concentration. Endocrinology 120: 1059–1068, 1987.
 181. Pardridge, W. M., E. M. Landaw, L. P. Miller, L. D. Braun, and W. H. Oldendorf. Carotid artery injection technique: bounds for bolus mixing by plasma and by brain. J. Cereb. Blood Flow Metab. 5: 576–583, 1985.
 182. Pardridge, W. M., and L. J. Mietus. Transport of protein‐bound steroid hormones into liver in vivo. Am. J. Physiol. 237 (Endocrinol. Metab. Gastrointest. Physiol. 6): E367–E372, 1979.
 183. Pardridge, W. M., and L. J. Mietus. Transport of steroid hormones through the rat blood–brain barrier. J. Clin. Invest. 64: 145–154, 1979.
 184. Pardridge, W. M., and L. J. Mietus. Influx of thyroid hormones into rat liver in vivo. J. Clin. Invest. 66: 367–374, 1980.
 185. Pardridge, W. M., L. J. Mietus, A. M. Frumar, B. J. Davidson, and H. L. Judd. Effects of human serum on transport of testosterone and estradiol in rat brain. Am. J. Physiol. 239 (Endocrinol. Metab. 2): E103–E108, 1980.
 186. Pardridge, W. M., T. L. Moeller, L. J. Mietus, and W. H. Oldendorf. Blood–brain barrier transport and brain sequestration of steroid hormones. Am. J. Physiol. 239 (Endocrinol. Metab. 2): E96–E102, 1980.
 187. Pardridge, W. M., B. N. Premachandra, and G. Fierer. Transport of thyroxine bound to human prealbumin into rat liver. Am. J. Physiol. 248 (Gastrointest. Liver Physiol. 11): G545–G550, 1985.
 188. Pardridge, W. M., R. Sakiyama, and G. Fierer. Transport of propranolol and lidocaine through the rat blood–brain barrier. J. Clin. Invest. 71: 900–908, 1983.
 189. Pardridge, W. M., R. Sakiyama, and H. L. Judd. Protein‐bound corticosteroid in human serum is selectively transported into rat brain and liver in vivo. J. Clin. Endocrinol. Metab. 57: 160–165, 1983.
 190. Pardridge, W. M., M. F. Slag, J. E. Morley, M. K. Elson, R. B. Shafer, and L. J. Mietus. Hepatic bioavailability of serum thyroid hormones in nonthyroidal illness. J. Clin. Endocrinol. Metab. 53: 913–916, 1981.
 191. Patlak, C. S., and O. B. Paulson. The role of unstirred layers for water exchange across the blood–brain barrier. Microvasc. Res. 21: 117–127, 1981.
 192. Payne, D. W., and J. A. Katzenellenbogen. Binding specificity of rat α‐fetoprotein for a series of estrogen derivatives: studies using equilibrium and nonequilibrium binding techniques. Endocrinology 105: 743–753, 1979.
 193. Pemberton, P. A., P. E. Stein, M. B. Pepys, J. M. Potter, and R. W. Carrell. Hormone binding globulins undergo serpin conformational change in inflammation. Nature 336: 257–258, 1988.
 194. Perry, M. A. Capillary filtration and permeability coefficients calculated from measurements of interendothelial cell junctions in rabbit lung and skeletal muscle. Microvasc. Res. 19: 142–157, 1980.
 195. Perry, M. A., and D. N. Granger. Permeability of intestinal capillaries to small molecules. Am. J. Physiol. 241 (Gastroint. Liver Physiol. 4): G24–G30, 1981.
 196. Pervaiz, S., and K. Brew. Homology and structure–function correlations between α1‐acid glycoprotein and serum retinol‐binding protein and its relatives. FASEB J. 1: 209–214, 1987.
 197. Peters, T., Jr. Serum albumin. Adv. Protein Chem. 37: 161–245, 1985.
 198. Piafsky, K. M., and O. Borgå. Plasma protein binding of basic drugs. Clin. Pharmacol. Ther. 22: 545–549, 1977.
 199. Piafsky, K. M., O. Borgå, I. Odar‐Cederlöf, C. Johansson, and F. Sjöqvist. Increased plasma protein binding of propranolol and chlorpromazine mediated by disease‐induced elevations of plasma α1 acid glycoprotein. N. Engl. J. Med. 299: 1435–1439, 1978.
 200. Rahman, S. S., R. B. Billiar, R. Miguel, W. Johnson, and B. Little. The metabolic clearance rate, the brain extraction and distribution and the uterine extraction and retention of progesterone and R 5020 in estrogen‐treated ovariectomized rabbits. Endocrinology 101: 464–468, 1977.
 201. Rask, L., and P. A. Peterson. In vitro uptake of vitamin A from the retinol‐binding plasma protein to mucosal epithelial cells from the monkey's small intestine. J. Biol. Chem. 251: 6360–6366, 1976.
 202. Reed, R. G., and C. M. Burrington. The albumin receptor effect may be due to a surface‐induced conformational change in albumin. J. Biol. Chem. 264: 9867–9872, 1989.
 203. Refetoff, S., F. E. Dwulet, and M. D. Benson. Reduced affinity for thyroxine in two of three structural thyroxine‐binding prealbumin variants associated with familial amyloidotic polyneuropathy. J. Clin. Endocrinol. Metab. 63: 1432–1437, 1986.
 204. Reid, D. G., L. K. MacLachlan, M. Voyle, and P. D. Leeson. A proton and fluorine‐19 nuclear magnetic resonance and fluorescence study of the binding of some natural and synthetic thyromimetics to prealbumin (transthyretin). J. Biol. Chem. 264: 2013–2023, 1989.
 205. Renkin, E. M. Transport of potassium‐42 from blood to tissue in isolated mammalian skeletal muscles. Am. J. Physiol. 197: 1205–1210, 1959.
 206. Renkin, E. M. Transport pathways through capillary endothelium. Microvasc. Res. 15: 123–135, 1978.
 207. Renkin, E. M., S. D. Gray, and L. R. Dodd. Filling of microcirculation in skeletal muscles during timed India ink perfusion. Am. J. Physiol. 241 (Heart Circ. Physiol. 12): H174–H186, 1981.
 208. Renoir, J.‐M., C. Mercier‐Bodard, and E.‐E. Baulieu. Hormonal and immunological aspects of the phylogeny of sex steroid binding plasma protein. Proc. Natl. Acad. Sci. U.S.A. 77: 4578–4582, 1980.
 209. Riad‐Fahmy, D., G. F. Read R. F. Walker, and K. Griffiths. Steroids in saliva for assessing endocrine function. Endocr. Rev. 3: 367–395, 1982.
 210. Riant, P., S. Urien, E. Albengres, A. Renouard, and J. P. Tillement. Effects of the binding of imipramine to erythrocytes and plasma proteins on its transport through the rat blood–brain barrier. J. Neurochem. 51: 421–425, 1988.
 211. Ridgway, E. C., C. Longcope, and F. Maloof. Metabolic clearance and blood production rates of estradiol in hyperthyroidism. J. Clin. Endocrinol. Metab. 41: 491–497, 1975.
 212. Robbins, J., and J. E. Rall. Effects of triiodothyronine and other thyroxine analogues on thyroxine‐binding in human serum. J. Clin. Invest. 34: 1331–1338, 1955.
 213. Robbins, J., J. E. Rall, and P. Gorden. The thyroid and iodine metabolism. In: Duncan's Disease of Metabolism, edited by P. K. Bondy and L. E. Rosenberg. Philadelphia: Saunders, 1974, p. 1009–1023.
 214. Roberts, M. S., and M. Rowland. Hepatic elimination‐dispersion model. J. Pharm. Sci. 74: 585–587, 1985.
 215. Rosenoer, V. M., and M. A. Rothschild. The extravascular transport of albumin. In: Plasma Protein Metabolism, edited by M. A. Rothschild and T. Waldmann. New York: Academic, 1970, p. 111–127.
 216. Rosenthal, H. E., W. R. Slaunwhite, Jr., and A. A. Sandberg. Transcortin: A corticosteroid‐binding protein of plasma. X. Cortisol and progesterone interplay and unbound levels of these steroids in pregnancy. J. Clin. Endocrinol. 29: 352–367, 1969.
 217. Rosner, W. The functions of corticosteroid‐binding globulin and sex hormone–binding globulin: recent advances. Endocr. Rev. 11: 80–91, 1990.
 218. Rouaze‐Romet, M., R. Vranckx, L. Savu, and E. A. Nunez. Structural and functional microheterogeneity of rat thyroxine‐binding globulin during ontogenesis. Biochem. J. 286: 125–130, 1992.
 219. Rowland, M., D. Leitch, G. Fleming, and B. Smith. Protein binding and hepatic clearance: discrimination between models of hepatic clearance with diazepam, a drug of high intrinsic clearance, in the isolated perfused rat liver preparation. J. Pharmacokinet. Biopharmet. 12: 129–147, 1984.
 220. Rudd, B. T., N. M. Duignan, and D. R. London. A rapid method for the measurement of sex hormone binding globulin capacity of sera. Clin. Chim. Acta 55: 165–178, 1974.
 221. Ruder, H., P. Corvol, J. A. Mahoudeau, G. T. Ross, and M. B. Lipsett. Effects of induced hyperthyroidism on steroid metabolism in man. J. Clin. Endocrinol. 33: 382–387, 1971.
 222. Rushbrook, J. I., E. Becker, G. C. Schussler, and C. M. Divino. Identification of a human serum albumin species associated with familial dysalbuminemic hyperthyroxinemia. J. Clin. Endocrinol. Metab. 80: 461–467, 1995.
 223. Ruutiainen, K., E. Sannikka, R. Santti, R. Erkkola, and H. Adlercreutz. Salivary testosterone in hirsutism: correlations with serum testosterone and the degree of hair growth. J. Clin. Endocrinol. Metab. 64: 1015–1020, 1987.
 224. Sakiyama, R., W. M. Pardridge, and H. L. Judd. Effects of human cirrhotic serum on estradiol and testosterone transport into rat brain. J. Clin. Endocrinol. Metab. 54: 1140–1144, 1982.
 225. Sakiyama, R., W. M. Pardridge, and N. A. Musto. Influx of testosterone‐binding globulin (TeBG) and TeBG‐bound sex steroid hormones into rat testis and prostate. J. Clin. Endocrinol. Metab. 67: 98–103, 1988.
 226. Salhany, J. M., and R. Cassoly. Kinetics of p‐mercuribenzoate binding to sulfhydryl groups on the isolated cytoplasmic fragment of band 3 protein. J. Biol. Chem. 264: 1399–1404, 1989.
 227. Scheider, W. The rate of access to the organic ligand‐binding region of serum albumin is entropy controlled. Proc. Natl. Acad. Sci. U.S.A. 76: 2283–2287, 1979.
 228. Schnitzer, J. E., W. W. Carley, and G. E. Palade. Specific albumin binding to microvascular endothelium in culture. Am. J. Physiol. 254 (Heart Circ. Physiol. 23): H425–H437, 1988.
 229. Schwartz, H. L., D. Trence, J. H. Oppenheimer, N. S. Jiang, and D. B. Jump. Distribution and metabolism of l‐ and d‐triiodothyronine (T3) in the rat: preferential accumulation of l‐T3 by hepatic and cardiac nuclei as a probable explanation of the differential biological potency of T3 enantiomers. Endocrinology 113: 1236–1243, 1983.
 230. Shand, D. G., R. H. Cotham, and G. R. Wilkinson. Perfusion‐limited effects of plasma drug binding on hepatic drug extraction. Life Sci. 19: 125–130, 1976.
 231. Sholl, S. A., P. T. K. Toivola, and J. A. Robinson. The dynamics of testosterone and dihydrotestosterone metabolism in the adult male rhesus monkey. Endocrinology 105: 402–405, 1979.
 232. Shore, M. L. Biological applications of kinetic analysis of a two‐compartment open system. J. Appl. Physiol. 16: 771–782, 1961.
 233. Siiteri, P. K. Extraglandular oestrogen formation and serum binding of oestradiol: relationship to cancer. J. Endocrinol. 89: 119P–129P, 1981.
 234. Simionescu, M., N. Ghinea, A. Fixman, M. Lasser, L. Kukes, N. Simionescu, and G. E. Palade. The cerebral microvasculature of the rat: structure and luminal surface properties during early development. J. Submicrosc. Cytol. Pathol. 20: 243–261, 1988.
 235. Smith, R. G., P. K. Besch, B. Dill, and V. C. Buttram, Jr. Saliva as a matrix for measuring free androgens: comparison with serum androgens in polycystic ovarian disease. Fertil. Steril. 31: 513–517, 1979.
 236. Smith, T. W., and K. M. Skubitz. Kinetics of interactions between antibodies and haptens. Biochemistry. 14: 1496–1502, 1975.
 237. Snyder, S. M., R. R. Cavalieri, I. D. Goldfine, S. H. Ingbar, and E. C. Jorgensen. Binding of thyroid hormones and their analogues to thyroxine‐binding globulin in human serum. J. Biol. Chem. 251: 6489–6494, 1976.
 238. Soloff, M. S., M. J. Morrison, and T. L. Swartz. A comparison of the estrone‐estradiol‐binding proteins in the plasmas of prepubertal and pregnant rats. Steroids 20: 597–608, 1972.
 239. Stein, W. D. The Movement of Molecules Across Cell Membranes. New York: Academic, 1967, p. 65–125.
 240. Steiner, R. F., J. Roth, and J. Robbins. The binding of thyroxine by serum albumin as measured by fluorescence quenching. J. Biol. Chem. 241: 560–567, 1966.
 241. Steingold, K. A., D. W. Matt, L. Dua, T. L. Anderson, and G. D. Hodgen. Orosomucoid in human pregnancy serum diminishes bioavailability of the progesterone antagonist RU 486 in rats. Am. J. Obstet. Gynecol. 162: 523–524, 1990.
 242. Stollman, Y. R., U. Gärtner, L. Theilmann, and N. Ohmi. Hepatic bilirubin uptake in the isolated perfused rat liver is not facilitated by albumin binding. J. Clin. Invest. 72: 718–723, 1983.
 243. Stroupe, S. D., S.‐L. Cheng, and U. Westphal. Steroid–protein interactions. Arch. Biochem. Biophys. 168: 473–482, 1975.
 244. Stroupe, S. D., G. B. Harding, M. W. Forsthoefel, and U. Westphal. Kinetic and equilibrium studies on steroid interaction with human corticosteroid‐binding globulin. Biochemistry 17: 177–182, 1978.
 245. Sugihara, J., T. Imamura, S. Nagafuchi, J. Bonaventura, C. Bonaventura, and R. Cashon. Hemoglobin rahere, a human hemoglobin variant with amino acid substitution at the 2,3–diphosphogylcerate binding site. J. Clin. Invest. 76: 1169–1173, 1985.
 246. Sundelin, J., H. Melhus, S. Das, U. Eriksson, P. Lind, L. Trägårdh, P. A. Peterson, and L. Rask. The primary structure of rabbit and rat prealbumin and a comparison with the tertiary structure of human prealbumin. J. Biol. Chem. 260: 6481–6487, 1985.
 247. Sutherland, R. L., and M. R. Brandon. The thyroxine‐binding properties of rat and rabbit serum proteins. Endocrinology 98: 91–98, 1976.
 248. Suzuki, N., T. Yamaguchi, and H. Nakajima. Role of high‐density lipoprotein in transport of circulating bilirubin in rats. J. Biol. Chem. 263: 5037–5043, 1988.
 249. Swartz, S. K., and M. S. Soloff. The lack of estrogen binding by human α‐fetoprotein. J. Clin. Endocrinol. Metab. 39: 589–591, 1974.
 250. Tait, J. F., and S. Burstein. In vivo studies of steroid dynamics in man. In: The Hormones, edited by G. Pincus, K. V. Thimann, and E. B. Astwood. New York: Academic, 1964, vol. V, p. 441–557.
 251. Terasaki, T., Y. Deguchi, Y. Kasama, W. M. Pardridge, and A. Tsuji. Determination of in vivo steady‐state unbound drug concentration in the brain interstitial fluid by microdialysis. Int. J. Pharm. 81: 143–152, 1992.
 252. Terasaki, T., Y. Deguchi, H. Sato, K. Hirai, and A. Tsuji. In vivo transport of a dynorphin‐like analgesid peptide, E‐2078, through the blood–brain barrier. An application of brain microdialysis. Pharm. Res. 8: 815–820, 1991.
 253. Terasaki, T., D. M. Nowlin, and W. M. Pardridge. Differential binding of testosterone and estradiol to isoforms of sex hormone–binding globulin: selective alteration of estradiol binding in cirrhosis. J. Clin. Endocrinol. Metab. 67: 639–643, 1988.
 254. Terasaki, T., and W. M. Pardridge. Stereospecificity of triiodothyronine transport into brain, liver, and salivary gland: role of carrier‐ and plasma protein–mediated transport. Endocrinology 121: 1185–1191, 1987.
 255. Terasaki, T., and W. M. Pardridge. Differential binding of thyroxine and triiodothyronine to acidic isoforms of thyroid hormone binding globulin in human serum. Biochemistry 27: 3624–3628, 1988.
 256. Terasaki, T., W. M. Pardridge, and D. D. Denson. Differential effect of plasma protein binding of bupivacaine on its in vivo transfer into the brain and salivary gland of rats. J. Pharmacol. Exp. Ther. 239: 724–729, 1986.
 257. Thomas, T., S. Fletcher, G. C. T. Yeoh, and G. Schreiber. The expression of α‐acid glycoprotein mRNA during rat development. J. Biol. Chem. 264: 5784–5790, 1989.
 258. Thorens, B., H. F. Lodish, and D. Brown. Differential localization of two glucose transporter isoforms in rat kidney. Am. J. Physiol. 259 (Cell Physiol. 28): C296–C302, 1990.
 259. Tilley, W. D., D. J. Horsfall, M. A. McGee, D. W. Henderson, and V. R. Marshall. Distribution of oestrogen and androgen receptors between the stroma and epithelium of the guinea‐pig prostate. J. Steroid Biochem. 22: 713–719, 1985.
 260. Tracqui, P., P. Brézillon, J. F. Staub, Y. Morot‐Gaudry, M. Hamon, and A. M. Perault‐Staub. Model of brain serotonin metabolism. I. Structure determination‐parameter estimation. Am. J. Physiol. 244 (Regulatory Integrative Comp. Physiol. 15): R193–R205, 1983.
 261. Tracqui, P., Y. Morot‐Gaudry, J. F. Staub, P. Brézillon, A. M. Perault‐Staub, S. Bourgoin, and M. Hamon. Model of brain serotonin metabolism. II. Physiological interpretation. Am. J. Physiol. 244 (Regulatory Integrative Comp. Physiol. 15): R206–R215, 1983.
 262. Tsao, S. C., Y. Sugiyama, Y. Sawada, T. Iga, and M. Hanano. Kinetic analysis of albumin‐mediated uptake of warfarin by perfused rat liver. J. Pharmacokinet. Biopharm. 16: 165–181, 1988.
 263. Tsao, S. C., Y. Sugiyama, K. Shinmura, Y. Sawada, S. Nagase, T. Iga, and M. Hanano. Protein‐mediated hepatic uptake of rose bengal in analbuminemic mutant rats (NAR). Drug Metab. Disposit. Biol. Fate Chem. 16: 482–489, 1988.
 264. Urien, S., F. Brée, B. Testa, and J.‐P. Tillement. pH‐dependency of basic ligand binding to α1‐acid glycoprotein (orosomucoid). Biochem. J. 280: 277–280, 1991.
 265. Urien, S., J.‐L. Pinquier, B. Paquette, P. Chaumet‐Riffaud, J.‐R. Kiechel, and J. P. Tillement. Effect of the binding of isradipine and darodipine to different plasma proteins on their transfer through the rat blood–brain barrier. Drug binding to lipoproteins does not limit the transfer of drug. J. Pharmacol. Exp. Ther. 242: 349–353, 1987.
 266. Urien, S., R. Zini, M. Lemaire, and J. P. Tillement. Assessment of cyclosporine A interactions with human plasma lipoproteins in vitro and in vivo in the rat. J. Pharmacol. Exp. Ther. 253: 305–309, 1990.
 267. van Thiel, D. H. Feminization of chronic alcoholic men: a formulation. Yale J. Biol. Med. 52: 219–225, 1979.
 268. Vermeulen, A. Influence of anabolic steroids on secretion and metabolism of cortisol. In: Structure and Metabolism of Corticosteroids, edited by J. R. Pasqualini and M. F. Jayle. New York: Academic, 1964, p. 109–116.
 269. Vermeulen, A. Transport and distribution of androgens at different ages. In: Androgens and Antiandrogens, edited by L. Martini and M. Motta. New York: Raven, 1977, p. 53–65.
 270. Vermeulen, A., and S. Andó. Metabolic clearance rate and interconversion of androgens and the influence of the free androgen fraction. J. Clin. Endocrinol. Metab. 48: 320–326, 1979.
 271. Vermeulen, A., L. Verdonck, M. Van der Straeten, and N. Orie. Capacity of the testosterone‐binding globulin in human plasma and influence of specific binding of testosterone on its metabolic clearance rate. J. Clin. Endocrinol. 29: 1470–1480, 1969.
 272. Vigersky, R. A., S. Kono, M. Sauer, M. B. Lipsett, and D. L. Loriaux. Relative binding of testosterone and estradiol to testosterone–estradiol‐binding globulin. J. Clin. Endocrinol. Metab. 49: 899–904, 1979.
 273. Wang, C., S. Plymate, E. Nieschlag, and C. A. Paulsen. Salivary testosterone in men: further evidence of a direct correlation with free serum testosterone. J. Clin. Endocrinol. Metab. 53: 1021–1024, 1981.
 274. Weideman, M. P. Architecture. In: Handbook of Physiology: The Cardiovascular System. Microcirculation, edited by E. M. Renkin and C. C. Michel. Bethesda, MD: Am. Physiol. Soc. 1984, sect. 2, vol. IV., pt. 1, chap. 2, p. 11–40.
 275. Weisiger, R. A. Dissociation from albumin: a potentially rate‐limiting step in the clearance of substances by the liver. Proc. Natl. Acad. Sci. U.S.A. 82: 1563–1567, 1985.
 276. Weisiger, R., J. Gollan, and R. Ockner. Receptor for albumin on the liver cell surface may mediate uptake of fatty acids and other albumin‐bound substances. Science 211: 1048–1051, 1981.
 277. Weiss, R. E., T. Sunthornthepvarakul, P. Angkeow, D. Marcus‐Bagley, N. Cox, C. A. Alper, and S. Refetoff. Linkage of familial dysalbuminemic hyperthyroxinemia to the albumin gene in a large Amish kindred. J. Clin. Endocrinol. Metab. 80: 116–121, 1995.
 278. Westergren, I., B. Nyström, A. Hamberger, and B. B. Johansson. Intracerebral dialysis and the blood–brain barrier. J. Neurochem. 64: 229–234, 1995.
 279. Westphal, U. Steroid‐binding serum globulins: recent results. In: Receptor and Hormone Action, edited by B. W. O'Malley and L. Birnbaumer. New York: Academic, 1978, vol. 2, p. 443–472.
 280. Whittem, T., and D. C. Ferguson. Kinetics of triiodothyronine dissociation from bovine serum albumin: modification of the resin capture method with subsequent computer modeling. Endocrinology 127: 2190–2198, 1990.
 281. Wilting, J., J. M. H. Kremer, A. P. Ijzerman, and S. G. Schulman. The kinetics of the binding of warfarin to human serum albumin as studied by stopped‐flow spectrophotometry. Biochim. Biophys. Acta 706: 96–104, 1982.
 282. Winkler, K., S. Keiding, and N. Tygstrup. Clearance as a quantitative measure of liver function. In: The Liver: Quantitative Aspects of Structure and Functions, edited by P. Paumgartners and P. Presig. Basel: Karger, 1973, p. 144–155.
 283. Woeber, K. A., and S. H. Ingbar. The contribution of thyroxine‐binding prealbumin to the binding of thyroxine in human serum, as assessed by immunoadsorption. J. Clin. Invest. 47: 1710–1721, 1968.
 284. Yamamoto, T., K. Doi, K. Ichihara, and K. Miyai. Reevaluation of measurement of serum free thyroxine by equilibrium dialysis based on computational analysis of the interaction between thyroxine and its binding proteins. J. Clin. Endocrinol. Metab. 50: 882–888, 1980.
 285. Yergey, J. A., and M. P. Heyes. Brain eicosanoid formation following acute penetration injury as studied by in vivo microdialysis. J. Cereb. Blood Flow Metab. 10: 143–146, 1990.
 286. Zaninovich, A. A., H. Farach, C. Ezrin, and R. Volpé. Lack of significant binding of l‐triiodothyronine by thyroxine‐binding globulin in vivo as demonstrated by acute disappearance of 131I‐labeled triiodothyronine. J. Clin. Invest. 45: 1290–1301, 1966.
 287. Zaninovich, A. A., R. Volpé, and C. Ezrin. Effects of variations of thyroxine‐binding globulin capacity on the disappearance of triiodothyronine from the plasma. J. Clin. Endocrinol. 29: 1601–1607, 1969.
 288. Zucker, S. D., W. Goessling, and J. L. Gollan. Kinetics of bilirubin transfer betweenserum albumin and membrane vesicles. J. Biol. Chem. 270: 1074–1081, 1995.

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William M. Pardridge. Targeted Delivery of Hormones to Tissues by Plasma Proteins. Compr Physiol 2011, Supplement 20: Handbook of Physiology, The Endocrine System, Cellular Endocrinology: 335-382. First published in print 1998. doi: 10.1002/cphy.cp070114