Rau S E, Bend J R, Arnold M O, Tran L T, Spence J D, Bailey D G
Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada.
Clin Pharmacol Ther. 1997 Apr;61(4):401-9. doi: 10.1016/S0009-9236(97)90190-9.
To investigate the single dose-response effects of grapefruit juice on terfenadine disposition and electrocardiographic measurements.
Twelve healthy males received 250 ml water or regular- or double-strength grapefruit juice with 60 mg terfenadine in a randomized crossover trial. Plasma concentrations of the cardiotoxic agent terfenadine and the active antihistaminic metabolite terfenadine carboxylate were determined over 8 hours. The QTc interval was monitored.
Terfenadine concentrations were measurable (> 1 ng/ml) in 27 (20%; p < 0.001) and 39 (30%; p < 0.001) samples from individuals treated with regular- and double-strength grapefruit juice, respectively, compared to only four (3%) samples with water. Terfenadine plasma peak drug concentration (Cmax) was also higher. Terfenadine carboxylate area under the plasma drug concentration-time curve (AUC), Cmax, and time to reach Cmax (tmax) were increased by both strengths of juice. However, terfenadine carboxylate apparent elimination half-life (t1/2) was not altered. The magnitude of the interaction of terfenadine carboxylate AUC and Cmax ranged severalfold and correlated among individuals for regular-strength (r2 = 0.87; p < 0.0001) and double-strength (r2 = 0.78; p < 0.0001) grapefruit juice. No differences in the pharmacokinetics of terfenadine and terfenadine carboxylate were observed between the two strengths of grapefruit juice. QTc interval was not altered.
A normal amount of regular-strength grapefruit juice produced maximum single-dose effects on terfenadine and carboxylic acid metabolite pharmacokinetics. The mechanism likely involved reduced presystemic drug elimination by inhibition of more than one metabolic pathway. The extent of the interaction was not sufficient to produce electrocardiographic changes. However, the pharmacokinetic effects were highly variable among individuals. This study further enhances the awareness of the potential for a serious interaction between grapefruit juice and terfenadine.
研究葡萄柚汁对特非那定处置及心电图测量的单剂量反应效应。
在一项随机交叉试验中，12名健康男性分别饮用250毫升水、常规浓度或双倍浓度葡萄柚汁，并服用60毫克特非那定。在8小时内测定心脏毒性药物特非那定及其活性抗组胺代谢物特非那定羧酸酯的血浆浓度。监测QTc间期。
与仅饮用4份（3%）水的样本相比，分别饮用常规浓度和双倍浓度葡萄柚汁的个体样本中，有27份（20%；p<0.001）和39份（30%；p<0.001）样本中可检测到特非那定浓度（>1纳克/毫升）。特非那定血浆药物峰浓度（Cmax）也更高。两种浓度的葡萄柚汁均使特非那定羧酸酯的血浆药物浓度-时间曲线下面积（AUC）、Cmax及达峰时间（tmax）增加。然而，特非那定羧酸酯的表观消除半衰期（t1/2）未改变。特非那定羧酸酯AUC与Cmax的相互作用强度在个体间相差数倍，且常规浓度（r2 = 0.87；p<0.0001）和双倍浓度（r2 = 0.78；p<0.0001）葡萄柚汁个体间存在相关性。两种浓度葡萄柚汁之间，特非那定及其羧酸酯的药代动力学无差异。QTc间期未改变。
正常量的常规浓度葡萄柚汁对特非那定及其羧酸代谢物的药代动力学产生最大单剂量效应。其机制可能是通过抑制多种代谢途径减少了药物的首过消除。相互作用的程度不足以引起心电图改变。然而，药代动力学效应在个体间差异很大。本研究进一步提高了对葡萄柚汁与特非那定之间潜在严重相互作用的认识。
