Vol. 26, Issue 2, 188-191, February 1998

SHORT COMMUNICATION
Mutual Inhibition between Quinine and Etoposide by Human Liver Microsomes
Evidence for Cytochrome P4503A4 Involvement in Their Major Metabolic Pathways

Xue-Jun Zhao, Takashi Kawashiro, and Takashi Ishizaki

Department of Clinical Pharmacology, Research Institute, International Medical Center of Japan (X.-J.Z., T.I.); R. and D. Division, Pharmaceutical Group, Nippon Kayaku Co., Ltd. (T.K.)

The mutual inhibition between quinine and etoposide with their major metabolic pathways (i.e. quinine 3-hydroxylation and etoposide 3-demethylation) was examined in vitro by human liver microsomes. Etoposide inhibited quinine 3-hydroxylation in a concentration-dependent manner with a mean IC₅₀ of 65 µM. The mean maximum inhibition by etoposide (100 µM) of quinine 3-hydroxylation was about 60%. Similarly, etoposide 3-demethylation was inhibited by quinine in a concentration-related manner with a mean IC₅₀ value of 90 µM. The mean maximum inhibition by quinine (100 M) of etoposide 3-demethylation was about 52%. An excellent correlation (r = 0.947, p < 0.01) between quinine 3-hydroxylase and etoposide 3-demethylase activities in six different human liver microsomes was observed. Two inhibitors of CYP3A4, ketoconazole (1 µM) and troleandomycin (100 µM), inhibited quinine 3-hydroxylation by about 90% and 80%, and etoposide 3-demethylation by about 75% and 65%, respectively. We conclude that quinine and etoposide mutually inhibit the metabolism of each other, consistent with the previous finding that CYP3A4 catalyzes the metabolism of both substrates.