Characterization of drug distribution and binding competition by two-chamber and multi-chamber distribution dialysis

Abstract

Binding competition between blood and tissue, a determinant of drug distribution, can be simulated and quantitated in vitro by distribution dialysis. In a study with a standardized two-chamber system, six model drugs, selected according to their ratio of plasma to tissue binding, were allowed to distribute between blood and eight tissue homogenates of rats. The tissue:blood concentration ratios were 1 for antipyrine, less than 1 for salicylic acid and phenylbutazone, slightly greater than 1 for pentobarbital and thiopental, and much greater than 1 for imipramine. Comparable values of tissue:blood ratios were obtained in rats in vivo. A modified dialysis system was developed which allows the simultaneous distribution of a drug between blood and four tissue homogenates. This multi-chamber system was used for homogenates of liver, lung, muscle, and adipose tissue. The drugs tested reached a first apparent distribution equilibrium after 2.5 to 4 h, comparable with the distribution in the two-chamber system, as a result of tissue:blood binding competition. In the following hours there was a redistribution as a result of binding competition among individual tissues, except in the case of pentobarbital. A minor redistribution from muscle to adipose tissue was observed with phenylbutazone, and from muscle to liver with imipramine. There was a considerable redistribution from all tissues, including blood, to adipose tissue with thiopental. In a sequential mode of operation this multi-chamber system was used to simulate the influence of the different perfusion rates of individual tissues by adding the homogenates of muscle and/or adipose tissue several hours after the other tissues.(ABSTRACT TRUNCATED AT 250 WORDS)