The roles of cytochrome P450 3A4 and 1A2 in the 3-hydroxylation of quininein vivo

Objective: To investigate the roles of CYP3A4 and CYP1A2 in the 3-hydroxyla tion of quinine in vivo. Methods: Ln a randomized, three-way crossover study, nine healthy Swedish v olunteers received single oral doses of quinine hydrochloride (500 mg), qui nine hydrochloride (500 mg) plus ketoconazole (100 mg twice daily for 3 day s), and quinine hydrochloride (500 mg) plus fluvoxamine (25 mg twice daily for 2 days) on three different occasions. Blood and urine samples were coll ected before quinine intake and up to 96 hours thereafter. Plasma and urine samples were analyzed for both quinine and its main metabolite 3-hydroxyqu inine with HPLC methods. Results: Coadministration with ketoconazole (which inhibits CYP3A4) decreas ed the mean apparent oral clearance of quinine significantly (P < .001) by 31% (from 8.7 to 6.0 L/h), whereas coadministration with fluvoxamine (which inhibits CYP1A2 and to some extent CYP2C19) had no significant effect (P > .05) on the mean apparent oral clearance of quinine, Coadministration with ketoconazole also decreased the mean area under the plasma concentration v ersus time curve (AUC) of 3-hydroxyquinine (from 28.4 to 19.7 mu mol.h.L-1; P < .001), whereas coadministration with fluvoxamine increased 3-hydroxyqu inine AUC significantly (from 28.4 to 30.2 mu mol.h.L-1; P < .05), Conclusion: Cytochrome P450 3A4 is important for the 3-hydroxylation of qui nine in vivo. On the other hand, CYP1A2 had no significant effect on this m etabolic pathway.