Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: Comparison with ritonavir
Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: Comparison with ritonavir
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DOI：
10.1016/j.clpt.2005.11.009
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发表时间：
2006-03-01
影响因子：
6.7
通讯作者：
Greenblatt, DJ
中科院分区：
文献类型：
--
作者：
Culm-Merdek, KE;von Moltke, LL;Greenblatt, DJ
背景和目标。急性摄入一定量的葡萄柚汁会抑制肠道细胞色素P450 (CYP) 3A酶，导致与许多药物的药代动力学相互作用。然而，长期饮用葡萄柚汁对CYP3A活性的影响尚未确定。三唑仑是一种CYP3A指数化合物，分4次（试验1-4）给3组志愿者（每组n = 6-7人），分别是：在联合治疗开始前1天，在联合治疗开始和结束时，在联合治疗停止后3天。3种联合处理（每天给药，连续10天）为：300 mL葡萄柚汁、400 mg利托那韦或300 mL水。结果：葡萄柚汁共处理（试验2）使三唑仑在血药浓度曲线下的面积比试验1对照组增加了50% (15.1 +/- 7.6 ng/mL.h比10.0 +/- 3.5 ng/mL.h, P < 0.05)，但半衰期没有变化。急性和长期暴露于葡萄柚汁（试验2和3）的效果相似，并且通过数字符号替代测试和脑电图β振幅测量苯二氮卓类激动剂效应的增强。在停止饮用葡萄柚汁3天后（试验4），动力学和动力学效应恢复到基线值（试验1）。在试验2 （553 +/- 422 ng/mL.h）和试验3 （287 +/- 299 ng/mL.h）期间，利托那韦导致血浆浓度曲线下的三唑仑面积比试验1对照组（13.3 +/- 16.3 ng/mL）增加了20倍以上。h)（两组比较P < 0.05）；数字符号替代试验和脑电图药效学同时升高。在试验4期间，三唑仑动力学恢复接近试验1的值，没有诱导的证据。水共处理未改变三唑仑动力学。结论：急性和长期暴露于葡萄柚汁产生定量相似的肠道抑制，而不是肝脏，CYP3A。停用西柚汁后3天内完全恢复。利托那韦对肠道和肝脏CYP3A均有显著抑制作用。延长利托那韦暴露时间，抑制作用是主要作用，利托那韦停药后3天几乎完全恢复到基线。
Background and Objectives. Acute ingestion of usual quantities of grapefruit juice produces inhibition of enteric cytochrome P450 (CYP) 3A enzymes, causing pharmacokinetic interactions with a number of drugs. However, the effect of extended exposure to grapefruit juice on CYP3A activity is not established.Methods. Triazolam, a CYP3A index compound, was administered to 3 cohorts of volunteers (n = 6-7 per group) on 4 occasions (trials 1-4), as follows: 1 day prior to cotreatment initiation, at the beginning and end of cotreatment, and 3 days after cotreatment discontinuation. The 3 cotreatments (daily administration for 10 consecutive days) were: 300 mL grapefruit juice, 400 mg ritonavir, or 300 mL water.Results: Grapefruit juice cotreatment (trial 2) increased the triazolam area under the plasma concentration curve by 50% compared to the trial 1 control (15.1 +/- 7.6 ng/mL.h versus 10.0 +/- 3.5 ng/mL.h, P < .05), but the half-life was not changed. Effects of acute and extended exposure to grapefruit juice (trials 2 and 3) were similar, and produced augmentation in benzodiazepine agonist effects measured by the Digit Symbol Substitution Test and electroencephalographic beta amplitude. Kinetic and dynamic effects reverted to baseline (trial 1) values at 3 days after grapefruit juice discontinuation (trial 4). Ritonavir caused a more than 20-fold increase in the triazolam area under the plasma concentration curve during trial 2 (553 +/- 422 ng/mL.h) and trial 3 (287 +/- 299 ng/mL.h) compared to the trial 1 control (13.3 +/- 16.3 ng/mL. h) (P < .05 for both comparisons); Digit Symbol Substitution Test and electroencephalographic pharmacodynamics increased in parallel. During trial 4, triazolam kinetics reverted close to trial 1 values, with no evidence of induction. Triazolam kinetics were not altered by water cotreatment.Conclusion: Acute and extended exposure to grapefruit juice produces quantitatively similar inhibition of enteric, but not hepatic, CYP3A. Recovery is complete within 3 days after grapefruit juice discontinuation. Ritonavir greatly inhibits both enteric and hepatic CYP3A. With extended exposure to ritonavir, inhibition is the predominant effect, and recovery to baseline is nearly complete 3 days after ritonavir discontinuation.