Metabolism of alfentanil by cytochrome P4503A (CYP3A) enzymes
Metabolism of alfentanil by cytochrome P4503A (CYP3A) enzymes
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DOI：
10.1124/dmd.104.002709
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发表时间：
2005-03-01
影响因子：
3.9
通讯作者：
Kharasch, ED
中科院分区：
文献类型：
--
作者：
Klees, TM;Sheffels, P;Kharasch, ED
合成阿片类药物阿芬太尼是一种镇痛药，也是肝脏和首过CYP 3A活性的体内探针。阿芬太尼是一种特别有用的CYP 3A探针，因为瞳孔直径变化是血浆浓度的替代品，从而提供CYP 3A的无创评估。阿芬太尼通过两种主要途径进行广泛的CYP 3A 4代谢，形成去甲阿芬太尼和N-苯基丙酰胺。本研究通过表达CYP 3A 5和CYP 3A 7以及CYP 3A 4，在有和没有共表达或外源性细胞色素B的情况下，评价了阿芬太尼体外代谢为去甲阿芬太尼和N-苯基丙酰胺（5）。还测定了CYP 3A抑制剂三乙酰竹桃霉素和酮康唑的作用。在不存在B的情况下，CYP 3A 4和3A 5的去甲芬太尼和N-苯基丙酰胺形成率基本相同（5），尽管代谢物形成率不同，而CYP 3A 7的代谢物形成率明显较低。CYP 3A 4和3A 5受到三乙酰竹桃霉素的抑制效力相同，而酮康唑对CYP 3A 4的抑制效力高一个数量级。细胞色素B（5）定性和定量改变了阿芬太尼代谢，B（5）共表达比外源性添加具有更大的影响。添加或共表达B（5）显著刺激了两种代谢物的形成，并改变了去甲芬太尼的形成，但没有改变N-苯基丙酰胺的形成，从表观的单位点米氏动力学变为多位点米氏动力学。这些结果表明，除了CYP 3A 4外，阿芬太尼还是CYP 3A 5的底物，CYP 3A抑制剂三乙酰竹桃霉素和酮康唑的作用具有CYP 3A酶选择性。阿芬太尼是少数几种在体外被CYP 3A 4和3A 5强烈代谢的CYP 3A底物之一。多态性CYP 3A 5表达可能导致阿芬太尼代谢的个体间差异。
The synthetic opioid alfentanil is an analgesic and an in vivo probe for hepatic and first-pass CYP3A activity. Alfentanil is a particularly useful CYP3A probe because pupil diameter change is a surrogate for plasma concentrations, thereby affording noninvasive assessment of CYP3A. Alfentanil undergoes extensive CYP3A4 metabolism via two major pathways, forming noralfentanil and N-phenylpropionamide. This investigation evaluated alfentanil metabolism in vitro to noralfentanil and N-phenylpropionamide, by expressed CYP3A5 and CYP3A7 in addition to CYP3A4, with and without coexpressed or exogenous cytochrome b(5). Effects of the CYP3A inhibitors troleandomycin and ketoconazole were also determined. Rates of noralfentanil and N-phenylpropionamide formation by CYP3A4 and 3A5 in the absence of b(5) were generally equivalent, although the metabolite formation ratio differed, whereas those by CYP3A7 were substantially less. CYP3A4 and 3A5 were equipotently inhibited by troleandomycin, whereas ketoconazole was an order of magnitude more potent toward CYP3A4. Cytochrome b(5) qualitatively and quantitatively altered alfentanil metabolism, with b(5) coexpression having a greater effect than exogenous addition. Addition or coexpression of b(5) markedly stimulated the formation of both metabolites and changed the formation of noralfentanil but not N-phenylpropionamide from apparent single-site to multisite Michaelis-Menten kinetics. These results demonstrate that alfentanil is a substrate for CYP3A5 in addition to CYP3A4, and the effects of the CYP3A inhibitors troleandomycin and ketoconazole are CYP3A enzyme-selective. Alfentanil is one of the few CYP3A substrates that is metabolized in vitro as avidly by both CYP3A4 and 3A5. Polymorphic CYP3A5 expression may contribute to interindividual variability in alfentanil metabolism.