Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteers.
BACKGROUND
Antimalarial mefloquine has a structure related to quinine. The major metabolite of quinine is 3-hydroxyquinine formed by cytochrome P450 3A4 (CYP3A4). Ketoconazole, a potent inhibitor of CYP3A4, is known to markedly increase plasma concentrations of various co-administered drugs including quinine.


OBJECTIVE
To assess the effect of ketoconazole on plasma concentrations of mefloquine in healthy 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 period. Plasma mefloquine and mefloquine carboxylic 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 mefloquine AUC0-t, t(1/2), and Cmax when compared with mefloquine alone by 79% (P < 0.001), 39% (P < 0.05) and 64% (P < 0.001) respectively. The AUC0-t , and Cmax of mefloquine carboxylic acid metabolite were decreased by 28% (P < 0.05) and 31% (P < 0.05), respectively when compared with mefloquine alone.


CONCLUSIONS
Co-administration with ketoconazole 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 mefloquine is co-administered with ketoconazole, drug-drug interactions should be recognized and the dose of mefloquine should be adjusted to maximize the therapeutic efficacy and to reduce the cost of therapy.
Ridtitid
W
W
Department of Pharmacology, Faculty of Science, Prince of Songkla University, Hat Yai, Thailand. wibool.r@psu.ac.th
Wongnawa
M
M
Mahatthanatrakul
W
W
Raungsri
N
N
Sunbhanich
M
M
D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000962:Antimalarials / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D007654:Ketoconazole / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D015767:Mefloquine / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D000935:Antifungal Agents; D000962:Antimalarials; D065607:Cytochrome P-450 Enzyme Inhibitors; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole; D015767:Mefloquine