Effects of Ketoconazole and Itraconazole on Plasma Concentrations of Quinine in Normal Healthy Volunteers

Abstract

Quinine is mainly metabolised by the cytochrome P450 3A4 isozyme (CYP3A4), whereas ketoconazole and itraconazole, potent inhibitors of CYP3A4, have been known to markedly increase plasma concentrations of various drugs which are concomitantly administered. The aims of the present study were to determine the effects of ketoconazole and itraconazole on the pharmacokinetics of quinine, and to examine a possible role of CYP3A4 on quinine metabolism in normal healthy volunteers. In a randomized crossover study with three phases and a two-week washout period, nine healthy Thai male volunteers ingested single doses of 300 mg quinine sulphate alone or after pretreatment with either 400 mg ketoconazole or 200 mg itraconazole orally once daily for 4 days. Blood samples were collected at specific time points over a 48-hour period. Plasma quinine concentrations were determined using HPLC for pharmacokinetic analysis. The results indicated that ketoconazole and itraconazole significantly increased the area under the plasma concentration-time curve (AUC_0-48) of quinine by 107% (P < 0.01) and 96% (P < 0.01), respectively; elimination half-life (T_1/2) by 70% (P < 0.01) and 71% (P < 0.01), respectively. Only ketoconazole significantly increased the maximum plasma concentration (C_max) by 29% (P < 0.01) and time to reach C_max (T _max) by 56% (P < 0.01), whereas itraconazole increased the C_max and T _max by 17% and 22%, respectively, but were not significantly different from the control phase. Therefore, the present study indicated that there was a significant interaction between ketoconazole or itraconazole and quinine in normal healthy volunteers since both ketoconazole and itraconazole elevated the AUC_0-48 of a single oral dose of 300 mg quinine sulphate by inhibition of quinine metabolism, probably via CYP3A4 activity in the liver. Ketoconazole had a slightly greater effect on the AUC_0-48 of quinine than that of itraconazole. Concomitant use of ketoconazole or itraconazole with quinine should be recognized in order to avoid drug interaction in malarial therapy.