Murray M, Butler A M
Storr Liver Unit, Department of Medicine, University of Sydney, Westmead Hospital, New South Wales, Australia.
J Pharmacol Exp Ther. 1996 Dec;279(3):1447-52.
Pharmacokinetic drug interactions involving the calcium channel blocker diltiazem (DTZ) have been attributed to inhibition of microsomal cytochrome P450 (P450)-mediated drug oxidation. Accumulation of certain DTZ metabolites during dosage with the drug, as well as dose-related differences in DTZ pharmacokinetics, suggests that DTZ metabolites may also participate in P450 inhibition. The present study evaluated a series of putative DTZ metabolites as inhibitors of major constitutive P450s in rat liver in vitro, in relation to DTZ biotransformation. The principal finding to emerge was that the N-demethylated metabolite of DTZ was a more potent competitive inhibitor than DTZ of CYP3A2-dependent testosterone 6 beta-hydroxylation. This P450 appeared to be the preferred target for inhibition, because the observed K/K(m) ratio for inhibition of CYP3A2-dependent steroid hydroxylation was approximately 4- and 100-fold lower than those for CYP2C11 and CYP2A1-dependent pathways, respectively. It was also established that N-desmethyl-DTZ was a major metabolite formed during microsomal DTZ biotransformation in rat liver in vitro. The other primary metabolites, desacetyl-DTZ and O-desmethyl-DTZ, were ineffective inhibitors of any pathways of steroid oxidation by P450s, but several other potential metabolites, which were not detected in microsomal incubations, also inhibited P450 activity. Consistent with previous reports, there was no evidence of P450 inactivation or complexation by DTZ, but the drug and its N-desmethyl metabolite generated binding interactions with ferric P450 in rat hepatic microsomes. Considered together, the findings of the present study establish that N-desmethyl-DTZ is a preferential inhibitor of CYP3A2 in rat hepatic microsomes, with greater potency than the parent drug. This is consistent with clinical reports in which this metabolite accumulates during multiple-dose therapy with DTZ. The competitive nature of the inhibitory interaction suggests that the eventual elimination of N-desmethyl-DTZ should restore normal hepatic oxidation capacity.
涉及钙通道阻滞剂地尔硫䓬（DTZ）的药代动力学药物相互作用被认为是由于微粒体细胞色素P450（P450）介导的药物氧化受到抑制。在使用该药物的过程中某些DTZ代谢物的蓄积以及DTZ药代动力学中与剂量相关的差异表明，DTZ代谢物也可能参与P450抑制作用。本研究评估了一系列假定的DTZ代谢物作为大鼠肝脏中主要组成型P450的体外抑制剂，并与DTZ生物转化相关。得出的主要发现是，DTZ的N-去甲基代谢物是比DTZ更强效的CYP3A2依赖性睾酮6β-羟基化竞争性抑制剂。这种P450似乎是抑制作用的首选靶点，因为观察到的抑制CYP3A2依赖性类固醇羟基化的K/K(m)比值分别比CYP2C11和CYP2A1依赖性途径低约4倍和100倍。还确定N-去甲基-DTZ是大鼠肝脏体外微粒体DTZ生物转化过程中形成的主要代谢物。其他主要代谢物，去乙酰基-DTZ和O-去甲基-DTZ，对P450介导的任何类固醇氧化途径均无抑制作用，但在微粒体孵育中未检测到的其他几种潜在代谢物也抑制P450活性。与先前的报道一致，但没有证据表明DTZ会使P450失活或形成复合物，但该药物及其N-去甲基代谢物在大鼠肝微粒体中与铁离子P450产生了结合相互作用。综合考虑，本研究结果表明N-去甲基-DTZ是大鼠肝微粒体中CYP3A2的优先抑制剂，其效力比母体药物更强。这与临床报道一致，即在DTZ多剂量治疗期间该代谢物会蓄积。抑制性相互作用的竞争性表明最终消除N-去甲基-DTZ应能恢复正常的肝脏氧化能力。
