Comprehensive Physiology Wiley Online Library

Determinants of Xenobiotic Transport at Biological Barriers

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Transport at Simple Barriers
1.1 Nonselective Transport
1.2 Diffusion
1.3 Criteria for Diffusion
1.4 Determinants of Permeability
1.5 Unstirred Water Layers
1.6 Solvent Drag
1.7 Diffusive Transport of Weak Electrolytes
1.8 Selective Transport
2 Transport at Complex Barriers
3 Concluding Remarks
Figure 1. Figure 1.

Solute diffusion in a two‐compartment system. Exchange of solute M between aqueous bulk phases 1 and 2 can be described in terms of two unidirectional fluxes: J12, a flux from compartment 1 to compartment 2; and J21, a flux from compartment 2 to compartment 1. The driving forces for these fluxes include the concentrations [M1] and [M1] of M in the two aqueous bulk phases, and the electric potentials Ψ1 and Ψ2 of the two aqueous bulk phases if M bears a net charge. Net movement of M(J) is the difference between the two unidirectional fluxes (J12J21). The difference between the two electric potentials (Ψ1 − Ψ2)) is the electric potential difference across the barrier (shaded) separating the two aqueous bulk phases.

Figure 2. Figure 2.

Solute diffusion across a lipid barrier. Exchange of the solute M between the aqueous bulk phases 1 and 2 can be described in terms of the following steps: diffusion in the aqueous phases; phase transitions at the lipid : water interfaces; and diffusion in the lipid phase of the barrier (shaded). In the steady state the concentrations of the solute in the lipid phase at the interfaces ([Mℓ1] and [Mℓ2]) are related to the concentrations of solute in the aqueous bulk phases ([M1] and [M2]) by the lipid : water partition coefficient of the solute.

Figure 3. Figure 3.

Influence of unstirred water layers on solute diffusion in a two‐compartment system. Resistance to the exchange of the solute M between aqueous bulk phases 1 and 2 is associated not only with the presence of the barrier (shaded) but also with U1 and U2, the unstirred water layers at the surfaces of the barrier. U1 and U2 may restrict the exchange of solute between the barrier and the aqueous bulk phases so that [MU1] and [MU1], the concentrations of solute at the surfaces of the barrier, are different from [M1] and [M2], the concentrations of solute in the respective bulk phases. Magnitudes of these differences are determined in part by d1 and d2, the thicknesses of the unstirred layers.

Figure 4. Figure 4.

Diffuse transport of weak acid in two‐compartment system. The aqueous bulk phases consist of solutions of the weak acid, HA. In each compartment the distribution of the acid between the ionized and nonionized forms is determined by the pKa of the acid, and by the pH values, pH1 and pH2, of the aqueous bulk phases. The barrier (shaded) is considered to be permeable to both the ionized and nonionized forms of the acid, so that the total exchange of weak acid between the aqueous bulk phases will include unidirectional fluxes of the nonionized acid, and , and of the anion and .

Figure 5. Figure 5.

Influence of (Pi/Pni) on transport of a weak acid in a two‐compartment system. Values of the flux ratio J12/J21 were calculated from Equation when Pi/Pni was varied in the range 100‐108. In constructing these curves the following data were used: pH1, = 7.0; pKa = 5.0; pH2 = 7.2 (A), 7.4 (B), 7.6 (C), 7.8 (D), or 8.0 (E); the electric potential difference was made negligibly small.

Figure 6. Figure 6.

Influence of pKa on transport of a weak acid in a two‐compartment system. Values of the flux ratio J12/J21 were calculated from Equation when pKa was varied in the range 1–9. The following data were used: pH1 = 7.0; pH2 = 7.5; (Pi/Pni) = 102 (B), 104 (C), 10−6 (D), or 10−8 (E); the electric potential difference was made negligibly small.

Figure 7. Figure 7.

Influence of electric potential difference on transport of a weak acid in a two‐compartment system. Values of the flux ratio J12/J21 were calculated from Equation when the electric potential difference across the barrier was varied in the range −25 through +25 mV. The following data were used: pH1 = 7.0; pH2 = 7.5; pKa = 5.0; (Pi/Pni) = 100 (A), 10−2 (B), 10−4 (C), or 10−8 (E).

Figure 8. Figure 8.

Comparison of A, the three‐compartment model for fluid transport of Curran and Macintosh with B, the structure of fluid‐transporting epithelia.

Adapted from Curran & MacIntosh and from Diamond & Tormey
Figure 9. Figure 9.

Three‐compartment model for weak electrolyte transport. Three compartments contain aqueous solutions of a weak acid. The compositions of the bulk phases (compartments 1 and 3) are identical, but the pH of the intermediate compartment (pH2) is different from that of the bulk phases (1 and 3, pH1). Thus the concentrations of the nonionized and ionized forms of the weak acid in the intermediate compartment ([pH2] and [A2]) will be different from the concentrations in the bulk phases ([HA1] and IA1]). Adjacent compartments are separated from each other by the barriers I and II. Both barriers are considered to be permeable to both the nonionized and ionized forms of the weak acid, but the two barriers differ in their abilities to discriminate between the ionized and nonionized forms of the weak acid. Conditions for net transport of the weak acid from one bulk phase to the other of this system are pH2 ≠ pH2 and .

Adapted from Jackson et al.
Figure 10. Figure 10.

Influence of pKa on transport of weak acids in the system shown in Figure . Values of the flux ratio were calculated from Equation from the following data: pH1 = 7.0; pH2 = 7.5; = 100; =10−2 (B), 10−4 (C), 10 −6 (D), 10−9 (E), or 10−10 (G).



Figure 1.

Solute diffusion in a two‐compartment system. Exchange of solute M between aqueous bulk phases 1 and 2 can be described in terms of two unidirectional fluxes: J12, a flux from compartment 1 to compartment 2; and J21, a flux from compartment 2 to compartment 1. The driving forces for these fluxes include the concentrations [M1] and [M1] of M in the two aqueous bulk phases, and the electric potentials Ψ1 and Ψ2 of the two aqueous bulk phases if M bears a net charge. Net movement of M(J) is the difference between the two unidirectional fluxes (J12J21). The difference between the two electric potentials (Ψ1 − Ψ2)) is the electric potential difference across the barrier (shaded) separating the two aqueous bulk phases.



Figure 2.

Solute diffusion across a lipid barrier. Exchange of the solute M between the aqueous bulk phases 1 and 2 can be described in terms of the following steps: diffusion in the aqueous phases; phase transitions at the lipid : water interfaces; and diffusion in the lipid phase of the barrier (shaded). In the steady state the concentrations of the solute in the lipid phase at the interfaces ([Mℓ1] and [Mℓ2]) are related to the concentrations of solute in the aqueous bulk phases ([M1] and [M2]) by the lipid : water partition coefficient of the solute.



Figure 3.

Influence of unstirred water layers on solute diffusion in a two‐compartment system. Resistance to the exchange of the solute M between aqueous bulk phases 1 and 2 is associated not only with the presence of the barrier (shaded) but also with U1 and U2, the unstirred water layers at the surfaces of the barrier. U1 and U2 may restrict the exchange of solute between the barrier and the aqueous bulk phases so that [MU1] and [MU1], the concentrations of solute at the surfaces of the barrier, are different from [M1] and [M2], the concentrations of solute in the respective bulk phases. Magnitudes of these differences are determined in part by d1 and d2, the thicknesses of the unstirred layers.



Figure 4.

Diffuse transport of weak acid in two‐compartment system. The aqueous bulk phases consist of solutions of the weak acid, HA. In each compartment the distribution of the acid between the ionized and nonionized forms is determined by the pKa of the acid, and by the pH values, pH1 and pH2, of the aqueous bulk phases. The barrier (shaded) is considered to be permeable to both the ionized and nonionized forms of the acid, so that the total exchange of weak acid between the aqueous bulk phases will include unidirectional fluxes of the nonionized acid, and , and of the anion and .



Figure 5.

Influence of (Pi/Pni) on transport of a weak acid in a two‐compartment system. Values of the flux ratio J12/J21 were calculated from Equation when Pi/Pni was varied in the range 100‐108. In constructing these curves the following data were used: pH1, = 7.0; pKa = 5.0; pH2 = 7.2 (A), 7.4 (B), 7.6 (C), 7.8 (D), or 8.0 (E); the electric potential difference was made negligibly small.



Figure 6.

Influence of pKa on transport of a weak acid in a two‐compartment system. Values of the flux ratio J12/J21 were calculated from Equation when pKa was varied in the range 1–9. The following data were used: pH1 = 7.0; pH2 = 7.5; (Pi/Pni) = 102 (B), 104 (C), 10−6 (D), or 10−8 (E); the electric potential difference was made negligibly small.



Figure 7.

Influence of electric potential difference on transport of a weak acid in a two‐compartment system. Values of the flux ratio J12/J21 were calculated from Equation when the electric potential difference across the barrier was varied in the range −25 through +25 mV. The following data were used: pH1 = 7.0; pH2 = 7.5; pKa = 5.0; (Pi/Pni) = 100 (A), 10−2 (B), 10−4 (C), or 10−8 (E).



Figure 8.

Comparison of A, the three‐compartment model for fluid transport of Curran and Macintosh with B, the structure of fluid‐transporting epithelia.

Adapted from Curran & MacIntosh and from Diamond & Tormey


Figure 9.

Three‐compartment model for weak electrolyte transport. Three compartments contain aqueous solutions of a weak acid. The compositions of the bulk phases (compartments 1 and 3) are identical, but the pH of the intermediate compartment (pH2) is different from that of the bulk phases (1 and 3, pH1). Thus the concentrations of the nonionized and ionized forms of the weak acid in the intermediate compartment ([pH2] and [A2]) will be different from the concentrations in the bulk phases ([HA1] and IA1]). Adjacent compartments are separated from each other by the barriers I and II. Both barriers are considered to be permeable to both the nonionized and ionized forms of the weak acid, but the two barriers differ in their abilities to discriminate between the ionized and nonionized forms of the weak acid. Conditions for net transport of the weak acid from one bulk phase to the other of this system are pH2 ≠ pH2 and .

Adapted from Jackson et al.


Figure 10.

Influence of pKa on transport of weak acids in the system shown in Figure . Values of the flux ratio were calculated from Equation from the following data: pH1 = 7.0; pH2 = 7.5; = 100; =10−2 (B), 10−4 (C), 10 −6 (D), 10−9 (E), or 10−10 (G).

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Michael J. Jackson, Victor H. Cohn. Determinants of Xenobiotic Transport at Biological Barriers. Compr Physiol 2011, Supplement 26: Handbook of Physiology, Reactions to Environmental Agents: 397-418. First published in print 1977. doi: 10.1002/cphy.cp090125