Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ibadan, Ibadan, Nigeria.
J Clin Pharm Ther. 2009 Dec;34(6):677-82. doi: 10.1111/j.1365-2710.2009.01064.x.
Halofantrine, an antimalarial drug used in endemic areas such as the tropics is mainly metabolized by CYP3A4 to the active metabolite N-desbutylhalofantrine. Fluconazole, an antifungal agent and an inhibitor of CYP3A4 is an established part of the therapy in HIV patients, who in turn are prone to malaria in the tropics. This study investigated the effect of fluconazole on the pharmacokinetics of halofantrine after concurrent administration of the two drugs.
The effect of fluconazole on the pharmacokinetics of the antimalarial drug halofantrine was evaluated in 15 healthy volunteers in a Latin Square crossover design. The subjects received a single oral dose of 500 mg halofantrine hydrochloride alone or with 50 mg fluconazole after an overnight fast. Venous blood samples were collected during the next 336 h and analysed by HPLC for halofantrine and its active metabolite N-desbutylhalofantrine.
Co-administration of fluconazole did not alter the pharmacokinetics of halofantrine significantly with the exception of elimination t(1/2) that was significantly increased by 25% (P < 0.05). In contrast, fluconazole significantly altered the pharmacokinetic parameters of the active metabolite by reducing C(max), AUC and metabolite ratio (N-desbutylhalofantrine/halofantrine) between 35 and 41% (P < 0.05) while increasing t(max) by 50%. The 90% confidence intervals of the ratio of the geometric means (with/without fluconazole) were contained within 80-125% for halofantrine but outside this range for N-desbutylhalofantrine.
The decreased plasma concentrations of the metabolite are presumably caused by metabolic inhibition of CYP3A4 by fluconazole. Although the therapeutic consequences of this interaction are not clear caution should be exercised when co-administering both drugs to avoid accumulation and subsequent cardiotoxic effects of halofantrine.
卤泛群是一种在热带等流行地区使用的抗疟药物，主要通过 CYP3A4 代谢为活性代谢物 N-去丁基卤泛群。氟康唑是一种抗真菌药物，也是 CYP3A4 的抑制剂，是 HIV 患者治疗的一部分，而 HIV 患者在热带地区容易感染疟疾。本研究调查了氟康唑同时给药对两种药物的药代动力学的影响。
采用拉丁方交叉设计，在 15 名健康志愿者中评估氟康唑对青蒿琥酯药代动力学的影响。受试者空腹一晚后单独口服 500mg 盐酸卤泛群或 50mg 氟康唑。在接下来的 336 小时内采集静脉血样，用 HPLC 分析青蒿琥酯及其活性代谢物 N-去丁基卤泛群。
氟康唑的合并用药并未显著改变青蒿琥酯的药代动力学，除消除半衰期（t1/2）增加 25%（P<0.05）外。相反，氟康唑通过减少 Cmax、AUC 和代谢物比值（N-去丁基卤泛群/青蒿琥酯）35%至 41%（P<0.05），同时将 tmax 增加 50%，显著改变了活性代谢物的药代动力学参数。几何均数比值（有/无氟康唑）的 90%置信区间包含在 80%至 125%之间，但 N-去丁基卤泛群除外。
代谢物血浆浓度降低可能是氟康唑对 CYP3A4 的代谢抑制所致。虽然这种相互作用的治疗后果尚不清楚，但在同时使用这两种药物时应谨慎，以避免青蒿琥酯的蓄积和随后的心脏毒性作用。
