Institute of Pharmaceutical Technology, Goethe University, 60438 Frankfurt am Main, Germany.
J Pharm Sci. 2013 Sep;102(9):3205-19. doi: 10.1002/jps.23611. Epub 2013 May 20.
One of the most prominent food-drug interactions is the inhibition of intestinal cytochrome P450 (CYP) 3A enzymes by grapefruit juice ingredients, and, as many drugs are metabolized via CYP 3A, this interaction can be of clinical importance. Calcium channel-blocking agents of the dihydropyridine type, such as felodipine and nifedipine, are subject to extensive intestinal first pass metabolism via CYP 3A, thus resulting in significantly enhanced in vivo exposure of the drug when administered together with grapefruit juice. Physiologically based pharmacokinetic (PBPK) modeling was used to simulate pharmacokinetics of a nifedipine immediate release formulation following concomitant grapefruit juice ingestion, that is, after inhibition of small intestinal CYP 3A enzymes. For this purpose, detailed data about CYP 3A levels were collected from the literature and implemented into commercial PBPK software. As literature reports show that grapefruit juice (i) leads to a marked delay in gastric emptying, and (ii) rapidly lowers the levels of intestinal CYP 3A enzymes, inhibition of intestinal first pass metabolism following ingestion of grapefruit juice was simulated by altering the intestinal CYP 3A enzyme levels and simultaneously decelerating the gastric emptying rate. To estimate the in vivo dispersion and dissolution behavior of the formulation, dissolution tests in several media simulating both the fasted and fed state stomach and small intestine were conducted, and the results from the in vitro dissolution tests were used as input function to describe the in vivo dissolution of the drug. Plasma concentration-time profiles of the nifedipine immediate release formulation both with and without simultaneous CYP 3A inhibition were simulated, and the results were compared with data gathered from the literature. Using this approach, nifedipine plasma profiles could be simulated well both with and without enzyme inhibition. A reduction in small intestinal CYP 3A levels by 60% was found to yield the best results, with simulated nifedipine concentration-time profiles within 20% of the in vivo observed results. By additionally varying the dissolution input of the PBPK model, a link between the dissolution characteristics of the formulation and its in vivo performance could be established.
一种最显著的食物-药物相互作用是葡萄柚汁成分抑制肠道细胞色素 P450（CYP）3A 酶，由于许多药物是通过 CYP 3A 代谢的，因此这种相互作用可能具有临床意义。二氢吡啶类钙通道阻滞剂，如非洛地平（felodipine）和硝苯地平（nifedipine），通过 CYP 3A 进行广泛的肠道首过代谢，因此当与葡萄柚汁一起给药时，药物的体内暴露显著增加。基于生理的药代动力学（PBPK）模型被用于模拟硝苯地平速释制剂在同时摄入葡萄柚汁后的药代动力学，即小肠 CYP 3A 酶被抑制后。为此，从文献中收集了关于 CYP 3A 水平的详细数据，并将其纳入商业 PBPK 软件。由于文献报道表明，葡萄柚汁（i）导致胃排空明显延迟，（ii）迅速降低肠道 CYP 3A 酶的水平，因此通过改变肠道 CYP 3A 酶的水平并同时减缓胃排空率来模拟摄入葡萄柚汁后肠道首过代谢的抑制。为了估计制剂的体内分散和溶解行为，进行了几种模拟空腹和进食状态胃和小肠的介质中的溶解试验，并将体外溶解试验的结果用作输入函数来描述药物的体内溶解。模拟了硝苯地平速释制剂在同时存在和不存在 CYP 3A 抑制的情况下的体内浓度-时间曲线，并将结果与文献中收集的数据进行了比较。使用这种方法，可以很好地模拟有和没有酶抑制的硝苯地平的血浆曲线。发现小肠 CYP 3A 水平降低 60%可产生最佳结果，模拟硝苯地平浓度-时间曲线与体内观察结果的差异在 20%以内。通过进一步改变 PBPK 模型的溶解输入，可以建立制剂的溶解特性与其体内性能之间的联系。
