Gross A S, Goh Y D, Addison R S, Shenfield G M
Department of Clinical Pharmacology, Royal North Shore Hospital, Sydney, New South Wales, Australia.
Clin Pharmacol Ther. 1999 Apr;65(4):395-401. doi: 10.1016/S0009-9236(99)70133-5.
Grapefruit juice increases the oral bioavailability of several drugs metabolized by cytochrome P450 3A4. This study investigated the influence of grapefruit juice on the pharmacokinetics of oral cisapride, a substrate of CYP3A4.
Fourteen healthy volunteers received in random order 10 mg cisapride (Prepulsid) with 250 mL water or grapefruit juice after an overnight fast. Blood samples were taken for 25 hours and urine was collected for 36 hours after dosing. Plasma concentrations of cisapride and urinary norcisapride were measured by HPLC. The influence of grapefruit juice on pharmacokinetic parameters (mean +/- SD) was assessed with the Wilcoxon matched pairs test for 13 subjects (1 subject did not fast as instructed).
Grapefruit juice increased cisapride maximum measured plasma concentration (Cmax; water, 65+/-398 ng/mL; grapefruit juice, 87+/-40 ng/mL; P = .009) and area under the plasma concentration-time curve from 0 to 25 hours [AUC(0-25); water, 418+/-280 h x ng/mL; grapefruit juice, 580+/-289 h x ng/mL; P = .005] and prolonged the time to reach Cmax (water, 1.26+/-0.36 hours; grapefruit juice, 1.72+/-0.55 hours; P = .02). Half-life was not affected. Urinary norcisapride recovery was similar and thus the partial apparent metabolic clearance to norcisapride was lower (P = .046) after grapefruit juice (89.5+/-41.2 mL/min) than after water (121.5+/-54.7 mL/min). There was considerable interindividual variation in the grapefruit juice effect [range of AUC(0-25) grapefruit juice/water ratio, 0.90 to 2.65).
Grapefruit juice increases the oral bioavailability of cisapride, with large interindividual variation in the change in Cmax and AUC. Because cisapride has a wide therapeutic index, the interaction may not be of major clinical significance for efficacy, but further studies are necessary at steady state to rule out the possibility of side effects in susceptible individuals.
葡萄柚汁可提高几种经细胞色素P450 3A4代谢的药物的口服生物利用度。本研究调查了葡萄柚汁对CYP3A4底物口服西沙必利药代动力学的影响。
14名健康志愿者在禁食过夜后，随机依次服用10mg西沙必利（普瑞博思），并用250mL水或葡萄柚汁送服。给药后采集血样25小时，收集尿液36小时。采用高效液相色谱法测定西沙必利的血浆浓度和尿中去甲西沙必利的含量。用Wilcoxon配对检验评估葡萄柚汁对13名受试者药代动力学参数（均值±标准差）的影响（1名受试者未按要求禁食）。
葡萄柚汁增加了西沙必利的最大实测血浆浓度（Cmax；水：65±398ng/mL；葡萄柚汁：87±40ng/mL；P = 0.009）以及0至25小时血浆浓度-时间曲线下面积[AUC(0 - 25)；水：418±280h×ng/mL；葡萄柚汁：580±289h×ng/mL；P = 0.005]，并延长了达到Cmax的时间（水：1.26±0.36小时；葡萄柚汁：1.72±0.55小时；P = 0.02）。半衰期未受影响。尿中去甲西沙必利的回收率相似，因此葡萄柚汁服用后（89.5±41.2mL/min）相对于水服用后（121.5±54.7mL/min），去甲西沙必利的部分表观代谢清除率较低（P = 0.046）。葡萄柚汁效应存在相当大的个体间差异[AUC(0 - 25)葡萄柚汁/水比值范围为0.90至2.65]。
葡萄柚汁可提高西沙必利的口服生物利用度，Cmax和AUC的变化存在较大个体间差异。由于西沙必利具有较宽的治疗指数，这种相互作用对疗效可能无重大临床意义，但需要在稳态下进行进一步研究，以排除易感个体出现副作用的可能性。
