Mutual inhibition between quinine and etoposide by human liver microsomes : Evidence for cytochrome P4503A4 involvement in their major metabolic pathways

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 IC50of 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.