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Effect of rifampin on plasma concentrations of mefloquine in healthy volunteers.
J Pharm Pharmacol. 2000 Oct; 52(10):1265-9.JP

Abstract

Mefloquine is a 4-quinolinemethanol compound structurally related to quinine. Quinine is mainly metabolized by the cytochrome P450 3A4 isozyme (CYP3A4), whereas rifampin, a potent inducer of CYP3A4, is known to markedly decrease plasma quinine concentration. Our aim was to study the effect of rifampin on the pharmacokinetics of mefloquine, and explore a possible role of CYP3A4 on mefloquine metabolism. In an open, two-phase crossover study, seven healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone, or 500 mg mefloquine plus a long-term administration of 600 mg rifampin. Blood samples were collected at specific time points over a 56-day period. Plasma mefloquine and its carboxylic acid metabolite were measured by HPLC for pharmacokinetic analysis. The results indicate that rifampin significantly decreased the area under the plasma concentration-time curve (AUC0 - infinity) of mefloquine by 68% (P < 0.01), maximum plasma concentration (Cmax) by 19% (P < 0.001), and elimination half-life (t1/2) by 63% (P < 0.01), whereas the time to reach Cmax (t(max)) of mefloquine was unaffected. The apparent oral clearance (CL) of mefloquine was significantly increased by 281% (P < 0.01). After administration of rifampin, the Cmax of the carboxylic acid metabolite of mefloquine was significantly increased by 47% (P < 0.05), whereas the t1/2 was significantly decreased by 39% (P < 0.01), and t(max) by 76% (P < 0.01). The AUC0 - infinity and CL of the mefloquine metabolite were increased by 30% and 25%, respectively, but were not significantly different from the control phase. The results indicate that rifampin reduces the plasma concentration of a single oral dose of 500 mg mefloquine by increasing metabolism of mefloquine in the liver and gut wall. The CYP3A4 isozyme most likely plays an important role in the enhanced metabolism of mefloquine. Simultaneous use of rifampin and mefloquine should be avoided to optimize the therapeutic efficacy of mefloquine and prevent the risk of Plasmodium falciparum resistance in malarial treatment.

Authors+Show Affiliations

Department of Pharmacology, Faculty of Science, Prince of Songkla University, Hat Yai, Thailand. rwibool@ratree.psu.ac.thNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11092571

Citation

Ridtitid, W, et al. "Effect of Rifampin On Plasma Concentrations of Mefloquine in Healthy Volunteers." The Journal of Pharmacy and Pharmacology, vol. 52, no. 10, 2000, pp. 1265-9.
Ridtitid W, Wongnawa M, Mahatthanatrakul W, et al. Effect of rifampin on plasma concentrations of mefloquine in healthy volunteers. J Pharm Pharmacol. 2000;52(10):1265-9.
Ridtitid, W., Wongnawa, M., Mahatthanatrakul, W., Chaipol, P., & Sunbhanich, M. (2000). Effect of rifampin on plasma concentrations of mefloquine in healthy volunteers. The Journal of Pharmacy and Pharmacology, 52(10), 1265-9.
Ridtitid W, et al. Effect of Rifampin On Plasma Concentrations of Mefloquine in Healthy Volunteers. J Pharm Pharmacol. 2000;52(10):1265-9. PubMed PMID: 11092571.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of rifampin on plasma concentrations of mefloquine in healthy volunteers. AU - Ridtitid,W, AU - Wongnawa,M, AU - Mahatthanatrakul,W, AU - Chaipol,P, AU - Sunbhanich,M, PY - 2000/11/25/pubmed PY - 2001/6/2/medline PY - 2000/11/25/entrez SP - 1265 EP - 9 JF - The Journal of pharmacy and pharmacology JO - J Pharm Pharmacol VL - 52 IS - 10 N2 - Mefloquine is a 4-quinolinemethanol compound structurally related to quinine. Quinine is mainly metabolized by the cytochrome P450 3A4 isozyme (CYP3A4), whereas rifampin, a potent inducer of CYP3A4, is known to markedly decrease plasma quinine concentration. Our aim was to study the effect of rifampin on the pharmacokinetics of mefloquine, and explore a possible role of CYP3A4 on mefloquine metabolism. In an open, two-phase crossover study, seven healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone, or 500 mg mefloquine plus a long-term administration of 600 mg rifampin. Blood samples were collected at specific time points over a 56-day period. Plasma mefloquine and its carboxylic acid metabolite were measured by HPLC for pharmacokinetic analysis. The results indicate that rifampin significantly decreased the area under the plasma concentration-time curve (AUC0 - infinity) of mefloquine by 68% (P < 0.01), maximum plasma concentration (Cmax) by 19% (P < 0.001), and elimination half-life (t1/2) by 63% (P < 0.01), whereas the time to reach Cmax (t(max)) of mefloquine was unaffected. The apparent oral clearance (CL) of mefloquine was significantly increased by 281% (P < 0.01). After administration of rifampin, the Cmax of the carboxylic acid metabolite of mefloquine was significantly increased by 47% (P < 0.05), whereas the t1/2 was significantly decreased by 39% (P < 0.01), and t(max) by 76% (P < 0.01). The AUC0 - infinity and CL of the mefloquine metabolite were increased by 30% and 25%, respectively, but were not significantly different from the control phase. The results indicate that rifampin reduces the plasma concentration of a single oral dose of 500 mg mefloquine by increasing metabolism of mefloquine in the liver and gut wall. The CYP3A4 isozyme most likely plays an important role in the enhanced metabolism of mefloquine. Simultaneous use of rifampin and mefloquine should be avoided to optimize the therapeutic efficacy of mefloquine and prevent the risk of Plasmodium falciparum resistance in malarial treatment. SN - 0022-3573 UR - https://www.unboundmedicine.com/medline/citation/11092571/Effect_of_rifampin_on_plasma_concentrations_of_mefloquine_in_healthy_volunteers_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&amp;sid=nlm:pubmed&amp;issn=0022-3573&amp;date=2000&amp;volume=52&amp;issue=10&amp;spage=1265 DB - PRIME DP - Unbound Medicine ER -