Fuhr U, Maier-Brüggemann A, Blume H, Mück W, Unger S, Kuhlmann J, Huschka C, Zaigler M, Rietbrock S, Staib A H
Institute for Pharmacology, Clinical Pharmacology, Universität zu Köln, Germany.
Int J Clin Pharmacol Ther. 1998 Mar;36(3):126-32.
The bioavailability of dihydropyridine calcium channel blockers following oral administration was shown to be increased by concomitant intake of grapefruit juice for all drugs of this class tested up to now. Here we report a randomized crossover interaction study on the effects of grapefruit juice on the pharmacokinetics of nimodipine and its metabolites. Eight healthy young men (4 smokers/4 nonsmokers) were included. Nimodipine was given as a single 30 mg tablet (Nimotop) with either 250 ml of water or 250 ml of grapefruit juice (751 mg naringin/l). Drug concentrations in plasma withdrawn up to 24 hours postdose were measured by GC-ECD, and model-independent pharmacokinetic parameters were estimated. The study was handled as an equivalence problem. Point estimators and ANOVA based 90% confidence intervals (CI) were calculated for the test (= grapefruit juice period) to reference (= water period) ratios using dose-normalized concentrations. The absence of a relevant interaction was assumed if the CIs were within the 0.67-1.50 range. Cmax for nimodipine reached 124% of the reference period (90% CI 0.76-2.01), AUC was increased to 151% (90% CI 114%-200%), respectively. The null hypothesis "relevant interaction" thus could not be rejected for the primary pharmacokinetic parameters AUC and Cmax. The ratios of metabolite AUC to parent drug AUC were slightly reduced with grapefruit juice intake. Additionally, there was evidence for a more pronounced hemodynamic response in the grapefruit juice period. To avoid the interaction, nimodipine should not be taken with grapefruit juice.
到目前为止，对于所有已测试的此类二氢吡啶类钙通道阻滞剂，口服给药后的生物利用度会因同时摄入葡萄柚汁而增加。在此，我们报告一项关于葡萄柚汁对尼莫地平及其代谢产物药代动力学影响的随机交叉相互作用研究。纳入了8名健康青年男性（4名吸烟者/4名非吸烟者）。尼莫地平以单次30毫克片剂（尼莫通）的形式给药，同时饮用250毫升水或250毫升葡萄柚汁（柚皮苷含量751毫克/升）。通过气相色谱 - 电子捕获检测法测量给药后24小时内采集的血浆中的药物浓度，并估算非模型依赖的药代动力学参数。该研究作为一个等效性问题处理。使用剂量标准化浓度，计算测试组（=葡萄柚汁期）与参照组（=水期）比值的点估计值和基于方差分析的90%置信区间（CI）。如果置信区间在0.67 - 1.50范围内，则假定不存在相关相互作用。尼莫地平的Cmax达到参照期的124%（90%CI 0.76 - 2.01），AUC分别增加到151%（90%CI 114% - 200%）。因此，对于主要药代动力学参数AUC和Cmax，“相关相互作用”的原假设不能被拒绝。摄入葡萄柚汁后，代谢产物AUC与母体药物AUC的比值略有降低。此外，有证据表明在葡萄柚汁期存在更明显的血流动力学反应。为避免相互作用，尼莫地平不应与葡萄柚汁同时服用。
