Pharmacokinetic and pharmacodynamic interaction between grapefruit juice and halofantrine
Pharmacokinetic and pharmacodynamic interaction between grapefruit juice and halofantrine
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DOI：
10.1067/mcp.2002.128148b
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发表时间：
2002-11-01
影响因子：
6.7
通讯作者：
Funck-Brentano, C
中科院分区：
文献类型：
--
作者：
Charbit, B;Becquemont, L;Funck-Brentano, C
背景：卤泛群是一种缩短QT间期的抗疟药，经细胞色素P450（CYP）3A 4代谢为N-脱丁基卤泛群。葡萄柚汁通过在肠上皮细胞水平抑制CYP 3A 4，增加了几种口服CYP 3A 4底物的生物利用度，因此可能增加卤泛群诱导的QT间期延长的风险。我们研究了葡萄柚汁对卤泛群生物利用度和口服给药相关的QT间期延长的影响。12名健康男性和女性志愿者接受500 mg卤泛群与250 mL水、橙子汁或葡萄柚汁（250 mL，每天一次，常规规格，持续3天，在卤泛群给药前12小时一次），在交叉研究期间以随机顺序。在随后的168小时内研究了卤泛群和N-脱丁基卤泛群的血浆药代动力学和QTc间期。与水相比，葡萄柚汁使卤泛群的血浆浓度-时间曲线下面积（AUC）和血浆峰浓度增加2.8倍+/- 1.5倍（P < .0001）和3.2倍+/-1.3倍（P < .0001）。N-脱丁基-卤泛群AUC随之降低2.4倍+/-1.6倍（P <0.01），但卤泛群消除半衰期无显著变化。最大QTc间期延长从卤泛群用水给药时的17 +/- 6 ms增加到与葡萄柚汁给药时的31 +/- 12 ms（P < .0005）。多元回归分析显示，QTc间期延长与卤泛群（部分r = 0.432; P <0.0001）的相关性优于与N-去丁基卤泛群（部分r = 0.117; P <0.01）浓度的相关性。水和橙子汁研究periods.Conclusions之间没有显着差异：葡萄柚汁增加卤泛群的生物利用度和卤泛群诱导的QT间期延长。在卤泛群给药期间应禁用葡萄柚汁。
Background: Halofantrine, an antimalarial drug that prolongs the QT interval, is metabolized into N-debutyl-halofantrine by cytochrome P450 (CYP) 3A4. Grapefruit juice increases the bioavailability of several orally administered CYP3A4 substrates by inhibiting CYP3A4 at the enterocyte level and could therefore increase the risk of halofantrine-induced QT interval prolongation. We studied the effect of grapefruit juice on halofantrine bioavailability and on QT interval prolongation associated with its oral administration.Methods: Twelve healthy male and female volunteers received 500 mg of halofantrine with 250 mL of water, orange juice, or grapefruit juice (250 mL once a day of regular strength for 3 days and once at 12 hours before halofantrine administration), in a random order, during a crossover study. Plasma pharmacokinetics of halofantrine and N-debutyl-halofantrine and QTc interval duration were studied during the following 168 hours.Results: Compared with water, grapefruit juice increased halofantrine area under the plasma concentration versus time curve (AUC) and peak plasma concentration by 2.8-fold +/- 1.5-fold (P < .0001) and 3.2-fold +/- 1.3-fold (P < .0001), respectively. There was a concomitant 2.4-fold +/- 1.6-fold decrease in N-debutyl-halofantrine AUC (P < .01) but no significant change in halofantrine elimination half-life. Maximum QTc interval prolongation increased from 17 +/- 6 ms when halofantrine was administered with water to 31 +/- 12 ms when it was administered with grapefruit juice (P < .0005). Multiple regression analysis showed that QTc interval prolongation was better correlated with halofantrine (partial r = 0.432; P < .0001) than with N-debutyl-halofantrine (partial r = 0.117; P < .01) concentrations. There was no significant difference between the water and orange juice study periods.Conclusions: Grapefruit juice increases halofantrine bioavailability and halofantrine-induced QT interval prolongation. Grapefruit juice should be contraindicated during administration of halofantrine.