Animal modelling of human polymorphic drug oxidation--the metabolism of debrisoquine and phenacetin in rat inbred strains.

Abstract

The metabolism of debrisoquine (5 mg kg-1 orally) was investigated in females of 7 strains of rat. Two major metabolic pathways, those of 4- and 6-hydroxylation were found to be polymorphic. The DA strain eliminated in urine only 7-10% of the dose as 4-hydroxy-debrisoquine together with 31-55% debrisoquine while the corresponding values for the Lewis strain were 44-55% and 11-17% respectively. Accordingly, DA and Lewis rats were proposed as models for the human PM (poor metabolizer) and EM (extensive metabolizer) drug oxidation phenotypes. To further test this model, DA and Lewis rats were given phenacetin (200 mg kg-1 orally). This underwent O-de-ethylation to paracetamol (52-55%) and aromatic 2-hydroxylation (7-8%) in Lewis rats. The corresponding findings in DA rats were 35-40% O-de-ethylation and 12-13% 2-hydroxylation. It is suggested that, with respect to both debrisoquine and phenacetin, Lewis and DA inbred rat strains afford a model of oxidative drug metabolism for the human EM and PM phenotypes respectively.