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Drug Partitioning III

1965; Elsevier BV; Volume: 54; Issue: 11 Linguagem: Inglês

10.1002/jps.2600541108

1520-6017

James T. Doluisio, Joseph V. Swintosky,

Drug Transport and Resistance Mechanisms

The kinetics of drug transfer from a buffered aqueous phase (compartment A) through a lipid phase (compartment B) to another aqueous buffered phase (compartment C) are reported. These kinetics are obtained from an in vitro model system which in important respects mimics drug transfer during the absorptive process. Several kinetic cases were observed–namely, DA → DB, DA ⇌ DB, DA → DC, DA ⇌ DC, DA ⇌ DB ⇌ DC, and DA ⇌ DB → DC. The DA → DC and DA ⇌ DC cases are of particular interest since these are often assumed to be applicable to in vivo drug absorption. The DA → DC transfer is actually a subcase of either a DA ⇌ DB → DC or a DA → DB → DC transfer in which the concentration of DB is negligible throughout the transfer process. The DA ⇌ DC transfer is actually a subcase of a DA ⇌ DB ⇌ DC transfer in which the same condition applies. In these two cases it is evident that the rate of disappearance of DA equals the rate of appearance of DC. In other cases where transport into compartment C is occurring there may be an appreciable accumulation of DB, and only during a steady concentration of DB are the rates of disappearance of DA and the appearance of DC equal. In all experiments the ratio of equilibrium values attained for DA and DC agreed with the ratio predicted by the pH partition hypothesis. The kinetics of drug transfer from a buffered aqueous phase (compartment A) through a lipid phase (compartment B) to another aqueous buffered phase (compartment C) are reported. These kinetics are obtained from an in vitro model system which in important respects mimics drug transfer during the absorptive process. Several kinetic cases were observed–namely, DA → DB, DA ⇌ DB, DA → DC, DA ⇌ DC, DA ⇌ DB ⇌ DC, and DA ⇌ DB → DC. The DA → DC and DA ⇌ DC cases are of particular interest since these are often assumed to be applicable to in vivo drug absorption. The DA → DC transfer is actually a subcase of either a DA ⇌ DB → DC or a DA → DB → DC transfer in which the concentration of DB is negligible throughout the transfer process. The DA ⇌ DC transfer is actually a subcase of a DA ⇌ DB ⇌ DC transfer in which the same condition applies. In these two cases it is evident that the rate of disappearance of DA equals the rate of appearance of DC. In other cases where transport into compartment C is occurring there may be an appreciable accumulation of DB, and only during a steady concentration of DB are the rates of disappearance of DA and the appearance of DC equal. In all experiments the ratio of equilibrium values attained for DA and DC agreed with the ratio predicted by the pH partition hypothesis.