Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
Centre for Pharmacology and Therapeutics, Imperial College London, London, UK.
Basic Clin Pharmacol Toxicol. 2018 Apr;122(4):388-395. doi: 10.1111/bcpt.12933. Epub 2017 Dec 15.
The atypical antipsychotic agent clozapine (CLZ) is effective in many patients who are resistant to conventional antipsychotic drugs. Cytochromes P450 (CYPs) 1A2 and 3A4 oxidize CLZ to norCLZ and CLZ N-oxide in human liver. Concurrent treatment with inducers and inhibitors of CYP1A2 modulates CLZ elimination that disrupts therapy. Drug-drug interactions involving CYP3A4 are also significant but less predictable. To further characterize the factors underlying these interactions, we used samples from a cohort of human livers to assess variation in CLZ oxidation pathways in relation to intrinsic CYP3A4 and CYP1A2 activities and the effects of the corresponding selective inhibitors ketoconazole (0.2 and 2 μM) and fluvoxamine (1 and 10 μM). The CYP3A4-selective inhibitor ketoconazole (2 μM) impaired CLZ N-oxide formation in all 14 of the livers used in inhibition studies (≥50% inhibition) while the CYP1A2-selective inhibitor fluvoxamine (10 μM) decreased norCLZ formation in nine. Ketoconazole effectively inhibited CLZ metabolism in five of seven livers that catalysed CYP3A4-dependent testosterone 6β-hydroxylation at or above the median rate and in four other livers with lower intrinsic CYP3A4 activity. Similarly, fluvoxamine (10 μM) readily inhibited CLZ oxidation in seven livers with high CYP1A2-mediated 7-ethoxyresorufin O-deethylation activity (at or above the median) and three livers with lower intrinsic CYP1A2 activity. In three livers, CLZ biotransformation was impaired by both ketoconazole and fluvoxamine, consistent with a major role for both CYPs. These findings suggest that the intrinsic activities of CYPs 1A2 and 3A4 are unrelated to the response to CYP-selective inhibitors and that assessment of the activities in vivo may not assist the prediction of drug-drug interactions.
非典型抗精神病药物氯氮平（CLZ）对许多对抗精神病药物耐药的患者有效。细胞色素 P450（CYPs）1A2 和 3A4 在人肝中将 CLZ 氧化为去甲氯氮平和 CLZ N-氧化物。CYP1A2 的诱导剂和抑制剂的同时治疗会调节 CLZ 的消除，从而破坏治疗。涉及 CYP3A4 的药物-药物相互作用也很重要，但预测性较低。为了进一步描述这些相互作用的基础，我们使用来自人类肝脏队列的样本来评估 CLZ 氧化途径与内在 CYP3A4 和 CYP1A2 活性的关系，以及相应的选择性抑制剂酮康唑（0.2 和 2 μM）和氟伏沙明（1 和 10 μM）的作用。CYP3A4 选择性抑制剂酮康唑（2 μM）在所有 14 个用于抑制研究的肝脏中（≥50%抑制）均损害了 CLZ N-氧化物的形成，而 CYP1A2 选择性抑制剂氟伏沙明（10 μM）则减少了 9 个。酮康唑在 7 个以中等或高于中位数速率催化 CYP3A4 依赖性睾酮 6β-羟化的肝脏中的 5 个中有效抑制了 CLZ 代谢，在其他 4 个内在 CYP3A4 活性较低的肝脏中也是如此。同样，氟伏沙明（10 μM）很容易抑制 7 个具有高 CYP1A2 介导的 7-乙氧基resorufin O-脱乙基化活性（中位数或以上）的肝脏和 3 个内在 CYP1A2 活性较低的肝脏中的 CLZ 氧化。在 3 个肝脏中，CLZ 生物转化受到酮康唑和氟伏沙明的双重抑制，这表明这两种 CYP 都起着重要作用。这些发现表明，CYP1A2 和 3A4 的内在活性与对 CYP 选择性抑制剂的反应无关，并且体内活性评估可能无助于预测药物-药物相互作用。
