Kawashiro T, Yamashita K, Zhao X J, Koyama E, Tani M, Chiba K, Ishizaki T
R. and D. Division, Pharmaceutical Group, Nippon Kayaku Co., Ltd., Tokyo, Japan.
J Pharmacol Exp Ther. 1998 Sep;286(3):1294-300.
The metabolism of etoposide was investigated by using human liver microsomes and nine recombinant human cytochrome P450 (CYP) isoforms to identify the CYP isoform(s) involved in the major metabolic pathway (3'-demethylation) of etoposide as well as to evaluate the possible metabolic interactions with several antitumor or supporting agents. The 3'-demethylation of etoposide followed a Michaelis-Menten one-enzyme kinetic behavior in six human liver microsomal samples. The relationships were assessed with six different human liver microsomes between the 3'-demethylation of etoposide and metabolic activities for substrate probes of the respective CYP isoforms, showing a significant correlation (r = 0. 932, P < .01) only with 6beta-hydroxylation of testosterone, a marker substrate for CYP3A4. Inhibitor/substrate probes for CYP3A4, ketoconazole, troleandomycin, verapamil and cyclosporin, or supporting agents, vincristine and prednisolone, inhibited etoposide 3'-demethylation by human liver microsomes. p-Nitrophenol, a substrate for CYP2E1, also inhibited etoposide 3'-demethylation. Among the nine recombinant human CYP isoforms, CYP3A4 exhibited the highest catalytic activity with respect to etoposide 3'-demethylation, compared with the minor activities of CYP1A2 and 2E1. Collectively, these data suggest that etoposide 3'-demethylation is mediated mainly by CYP3A4 and to a minor extent by CYP1A2 and 2E1. Furthermore, some supporting agents (vincristine and prednisolone) and the substrates of CYP3A4, which may be coadministered with etoposide during the cancer chemotherapies, inhibit the etoposide 3'-demethylation activity in vitro. The results may provide clinical implications with respect to the possible metabolic interactions between etoposide and other drugs studied herein in patients with cancer undergoing etoposide concurrently with either of them.
通过使用人肝微粒体和九种重组人细胞色素P450（CYP）同工型来研究依托泊苷的代谢，以鉴定参与依托泊苷主要代谢途径（3'-去甲基化）的CYP同工型，并评估其与几种抗肿瘤或辅助药物之间可能的代谢相互作用。依托泊苷的3'-去甲基化在六个人肝微粒体样品中遵循米氏单酶动力学行为。评估了六种不同人肝微粒体中依托泊苷的3'-去甲基化与各CYP同工型底物探针的代谢活性之间的关系，结果显示仅与睾酮的6β-羟基化（CYP3A4的标志物底物）存在显著相关性（r = 0.932，P <.01）。CYP3A4的抑制剂/底物探针酮康唑、三乙酰竹桃霉素、维拉帕米和环孢素，或辅助药物长春新碱和泼尼松龙，均可抑制人肝微粒体对依托泊苷的3'-去甲基化。CYP2E1的底物对硝基苯酚也可抑制依托泊苷的3'-去甲基化。在九种重组人CYP同工型中，与CYP1A2和2E1的低活性相比，CYP3A4对依托泊苷的3'-去甲基化表现出最高的催化活性。总体而言，这些数据表明依托泊苷的3'-去甲基化主要由CYP3A4介导，CYP1A2和2E1介导的程度较小。此外，一些辅助药物（长春新碱和泼尼松龙）以及CYP3A4的底物（在癌症化疗期间可能与依托泊苷联合使用）在体外可抑制依托泊苷的3'-去甲基化活性。这些结果可能为正在接受依托泊苷治疗的癌症患者中依托泊苷与本文研究的其他药物之间可能的代谢相互作用提供临床启示。
