Dayer P, Balant L, Fabre J
Int J Clin Pharmacol Res. 1983;3(6):421-5.
Hepatic drug oxidation is a major source of interindividual variations in drug behaviour. A wide spread of the pharmacokinetic parameters of extensively oxidized drugs is a common observation. For such compounds, in the absence of polymodal distribution of the kinetic parameters, no distinct genetic influence can be detected. The discovery that the urinary excretion of debrisoquine and its main hydroxylated metabolite displays a bimodal pattern opened a new field in the study of hepatic metabolism. This new genetic polymorphism now concerns the oxidative metabolism of numerous substances such as antihypertensive agents, antidepressants, antiarrhythmic drugs and various other unrelated compounds. The poor metabolizer phenotype is observed in some 8% of individuals in European populations. We have shown that the oxidative metabolism of beta-adrenoceptor blocking drugs is under the same genetic control as debrisoquine. Using bufuralol as a test drug, we have studied the influence of polymorphic oxidation on interindividual variations of parent drug and metabolite plasma concentrations. It appears clearly that oxidation polymorphism is a major factor of variability in hepatic drug handling. This fact has important clinical and pharmaceutical implications.
肝脏药物氧化是药物行为个体间差异的主要来源。广泛氧化药物的药代动力学参数广泛分布是常见现象。对于这类化合物，在动力学参数不存在多峰分布的情况下，无法检测到明显的遗传影响。发现异喹胍及其主要羟基化代谢物的尿排泄呈现双峰模式，为肝脏代谢研究开辟了一个新领域。这种新的遗传多态性现在涉及多种物质的氧化代谢，如抗高血压药、抗抑郁药、抗心律失常药和各种其他不相关的化合物。在欧洲人群中，约8%的个体表现出代谢不良者表型。我们已经表明，β-肾上腺素受体阻断药的氧化代谢与异喹胍受相同的遗传控制。使用布呋洛尔作为测试药物，我们研究了多态性氧化对母体药物和代谢物血浆浓度个体间差异的影响。显然，氧化多态性是肝脏药物处理变异性的主要因素。这一事实具有重要的临床和药学意义。
