Marre F, Sanderink G J, de Sousa G, Gaillard C, Martinet M, Rahmani R
Institut National de la Santé et de la Recherche Médicale, Antíbes, France.
Cancer Res. 1996 Mar 15;56(6):1296-302.
Docetaxel metabolism mediated by cytochrome P450-dependent monooxygenases was evaluated in human liver microsomes and hepatocytes. In microsomes, the drug was converted into four major metabolites resulting from successive oxidations of the tert-butyl group on the synthetic side chain. Enzyme kinetics appeared to be biphasic with a V(max) and apparent K(m) for the high-affinity site of 9.2 pmol/min/mg and 1.1 microm, respectively. the intrinsic metabolic clearance in human liver microsomes (V(max)/K(m), 8.4 ml/min/g protein) was comparable to that in rat and dog liver microsomes, but lower in mouse liver microsomes. Although the metabolic profile was identical in all subjects, a large quantitative variation in docetaxel biotransformation rates was found in a human liver microsome library, with a ratio of 8.9 in the highest:lowest biotransformation rates. Docetaxel biotransformation was correlated significantly (0.7698; P < 0.0001) with erythromycin N-demethylase activity, but not with aniline hydroxylase or debrisoquine 4-hydroxylase. It was inhibited, both in human hepatocytes and in liver microsomes, by typical CYP3A substrates and/or inhibitors such as erythromycin, ketoconazole, nifedipine, midazolam, and troleandomycin. Docetaxel metabolism was induced in vitro in human hepatocytes by dexamethasone and rifampicin, both classical CYP3A inducers. These data suggest a major role of liver cytochrome P450 isoenzymes of the CYP3A subfamily in docetaxel biotransformation in humans. Finally, some Vinca alkaloids and doxorubicin were shown to inhibit docetaxel metabolism in human hepatocytes and liver microsomes. These findings may have clinical implications and should be taken into account in the design of combination cancer chemotherapy regimens.
在人肝微粒体和肝细胞中评估了细胞色素P450依赖性单加氧酶介导的多西他赛代谢。在微粒体中，该药物通过合成侧链上叔丁基的连续氧化转化为四种主要代谢物。酶动力学似乎呈双相性，高亲和力位点的V(max)和表观K(m)分别为9.2 pmol/分钟/毫克和1.1微摩尔。人肝微粒体中的内在代谢清除率（V(max)/K(m)，8.4毫升/分钟/克蛋白质）与大鼠和狗肝微粒体中的相当，但在小鼠肝微粒体中较低。尽管所有受试者的代谢谱相同，但在人肝微粒体文库中发现多西他赛生物转化速率存在很大的定量差异，最高与最低生物转化速率之比为8.9。多西他赛生物转化与红霉素N-脱甲基酶活性显著相关（0.7698；P<0.0001），但与苯胺羟化酶或异喹胍4-羟化酶无关。在人肝细胞和肝微粒体中，它都受到典型的CYP3A底物和/或抑制剂如红霉素、酮康唑、硝苯地平、咪达唑仑和醋竹桃霉素的抑制。地塞米松和利福平这两种经典的CYP3A诱导剂在体外可诱导人肝细胞中的多西他赛代谢。这些数据表明CYP3A亚家族的肝细胞色素P450同工酶在人类多西他赛生物转化中起主要作用。最后，一些长春花生物碱和阿霉素被证明可抑制人肝细胞和肝微粒体中的多西他赛代谢。这些发现可能具有临床意义，在联合癌症化疗方案的设计中应予以考虑。
