Metabolism and elimination of quinine in healthy volunteers

Abstract

Objectives: The aims were to investigate: (1) The renal elimination of quinine and its metabolites 3-hydoxyquinine, 2'-quininone, (10R) and (10S)-11-dihydroxydihydroquinine and (2) the relative importance of CYP3A4, CYP1A2 and CYP2C19 for the formation of 2'-quininone, (10R) and (10S)-11-dihydroxydihydroquinine in vivo.

Methods: In a randomised three-way crossover study, nine healthy Swedish subjects received a single oral dose of quinine hydrochloride (500 mg), on three different occasions: (A) alone, (B) concomitantly with ketoconazole (100 mg twice daily for 3 days) and (C) concomitantly with fluvoxamine (25 mg twice daily for 2 days). Blood and urine samples were collected before quinine intake and up to 96 h thereafter. All samples were analysed by means of high-performance liquid chromatography.

Results: Co-administration with ketoconazole significantly increased the area under the plasma concentration versus time curve (AUC) of 2'-quininone, (10S)-11-dihydroxydihydroquinine, and (10R)-11-dihydroxydihydroquinine, the geometric mean ratios (90% CI) of the AUC were 1.9 (1.8, 2.0), 1.3 (1.1, 1.7) and 1.6 (1.4, 1.8), respectively. Co-administration with fluvoxamine had no significant effect on the mean AUC of any of the metabolites. A mean of 56% of the administered oral quinine dose was recovered in urine after hydrolysis with beta-glucuronidase relative to the 40% recovered before hydrolysis.

Conclusion: Quinine is eliminated in urine mainly as unchanged drug and as 3-hydroxyquinine. The major metabolite of quinine is 3-hydroxyquinine formed by CYP3A4. There is no evidence for the involvement of CYP3A4, 1A2 or 2C19 in the formation of 2'-quininone, (10S)-11-dihydroxydihydroquinine and (10R)-11-dihydroxydihydroquinine in vivo. Glucuronidation is an important pathway for the renal elimination of quinine, mainly as direct conjugation of the drug.