of antimalarial mefloquine in healthy human volunteers

structure related to quinine. The major metabolite of quinine is 3-hydroxyquinine formed by cyto-chrome P450 3A4 (CYP3A4). Ketoconazole, a potent inhibitor of CYP3A4, is known to mark-edly increase plasma concentrations of various co-administered drugs including quinine. Objective: To assess the effect of ketoconazole on plasma concentrations of mefloquine in heal-thy Thai male volunteers. Methods: In an open, randomized two-phase crossover study separated by a 1-month period, eight healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone or co-administration with 400 mg/day ketoconazole orally for 10 days. Serial blood samples were collected at specific time points for a 56-day per-iod. Plasma mefloquine and mefloquine carb-oxylic metabolite concentrations during 56 days were measured by a modified and validated high-performance liquid chromatographic method with UV detection. Results: Co-administration with ketoconazole markedly increased the mean values of mefloqu-ine AUC0)t, t1/2, and Cmax when compared with mefloquine alone by 79 % (P < 0Æ001), 39% (P < 0Æ05) and 64 % (P < 0Æ001) respectively. The AUC0)t, and Cmax of mefloquine carboxylic acid metabolite were decreased by 28 % (P < 0Æ05) and 31 % (P < 0Æ05), respectively when compared with mefloquine alone. Conclusions: Co-administration with ketoconaz-ole increased plasma mefloquine concentrations in healthy human volunteers. One of possible mechanisms of the increase in plasma mefloquine concentrations may be the result of the inhibition of CYP3A4 by ketoconazole. In case of mefloqu-ine is co-administered with ketoconazole, drug– drug interactions should be recognized and the dose of mefloquine should be adjusted to max-imize the therapeutic efficacy and to reduce the cost of therapy