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Vol. 286, Issue 3, 1294-1300, September 1998

A Study on the Metabolism of Etoposide and Possible Interactions with Antitumor or Supporting Agents by Human Liver Microsomes1

Takashi Kawashiro, Kouwa Yamashita, Xue-Jun Zhao, Eriko Koyama, Masayoshi Tani, Kan Chiba and Takashi Ishizaki

R. and D. Division, Pharmaceutical Group, Nippon Kayaku Co., Ltd. (T.K., K.Y.), Tokyo; Department of Clinical Pharmacology, Research Institute (X.J.Z., E.K., T.I.) and Division of General Surgery, Department of Surgery (M.T.), International Medical Center of Japan, Tokyo and Laboratory of Biochemical Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, Chiba University (K.C.), Chiba, Japan

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.

0022-3565/98/2863-1294$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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