Charbit Beny, Becquemont Laurent, Lepère Bénédicte, Peytavin Gilles, Funck-Brentano Christian
Division of Clinical Pharmacology and Clinical Investigation Center, Saint-Antoine University Hospital, Paris Cedex, France.
Clin Pharmacol Ther. 2002 Nov;72(5):514-23. doi: 10.1067/mcp.2002.128148b.
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.
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.
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.
Grapefruit juice increases halofantrine bioavailability and halofantrine-induced QT interval prolongation. Grapefruit juice should be contraindicated during administration of halofantrine.
卤泛群是一种可延长QT间期的抗疟药物，通过细胞色素P450（CYP）3A4代谢为N - 去丁基卤泛群。葡萄柚汁通过在肠细胞水平抑制CYP3A4增加几种口服CYP3A4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以及与其口服给药相关的QT间期延长的影响。
在一项交叉研究中，12名健康男性和女性志愿者按随机顺序分别用250毫升水、橙汁或葡萄柚汁（常规浓度，每天250毫升，共3天，并在服用卤泛群前12小时服用一次）送服500毫克卤泛群。在接下来的168小时内研究卤泛群和N - 去丁基卤泛群的血浆药代动力学以及QTc间期持续时间。
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）和血浆峰浓度分别增加了2.8倍±1.5倍（P <.0001）和3.2倍±1.3倍（P <.0001）。N - 去丁基卤泛群的AUC同时下降了2.4倍±1.6倍（P <.01），但卤泛群的消除半衰期无显著变化。最大QTc间期延长从服用卤泛群时用水送服的17±6毫秒增加到用葡萄柚汁送服时的31±12毫秒（P <.0005）。多元回归分析表明，QTc间期延长与卤泛群浓度（偏相关系数r = 0.432；P <.0001）的相关性优于与N - 去丁基卤泛群浓度（偏相关系数r = 0.117；P <.01）的相关性。用水和橙汁送服的研究期间无显著差异。
葡萄柚汁增加卤泛群的生物利用度以及卤泛群诱导的QT间期延长。服用卤泛群期间应禁用葡萄柚汁。
