人类多态性药物氧化的动物模型——大鼠近交系中异喹胍和非那西丁的代谢

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

作者信息

Al-Dabbagh S G, Idle J R, Smith R L

出版信息

J Pharm Pharmacol. 1981 Mar;33(3):161-4. doi: 10.1111/j.2042-7158.1981.tb13740.x.

DOI:10.1111/j.2042-7158.1981.tb13740.x

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.

摘要

在7个品系的雌性大鼠中研究了异喹胍（口服5毫克/千克）的代谢情况。发现4-羟基化和6-羟基化这两条主要代谢途径具有多态性。DA品系大鼠经尿液排出的剂量中，4-羟基异喹胍仅占7%-10%，异喹胍占31%-55%；而Lewis品系大鼠的相应数值分别为44%-55%和11%-17%。因此，DA和Lewis大鼠被提议作为人类药物氧化代谢表型中慢代谢者（PM）和快代谢者（EM）的模型。为了进一步验证该模型，给DA和Lewis大鼠口服非那西丁（200毫克/千克）。在Lewis大鼠中，非那西丁发生O-脱乙基反应生成对乙酰氨基酚（52%-55%）和芳香族2-羟基化反应（7%-8%）。在DA大鼠中的相应结果是O-脱乙基反应为35%-40%，2-羟基化反应为12%-13%。研究表明，就异喹胍和非那西丁而言，Lewis和DA近交系大鼠分别为人类EM和PM表型提供了氧化药物代谢模型。