Kupferschmidt H H, Ha H R, Ziegler W H, Meier P J, Krähenbühl S
Division of Clinical Pharmacology and Toxicology, University Hospital, Zürich, Switzerland.
Clin Pharmacol Ther. 1995 Jul;58(1):20-8. doi: 10.1016/0009-9236(95)90068-3.
To investigate the effects of grapefruit juice on the pharmacokinetics and dynamics of midazolam.
Eight healthy male subjects participated in this open crossover study. Intravenous (5 mg) or oral (15 mg) midazolam was administered after pretreatment with water or grapefruit juice. We measured the pharmacokinetics and pharmacodynamics (reaction time, Digit Symbol Substitution Test [DSST], general impression judged by the investigators, and drug effect judged by the subjects) of midazolam and the pharmacokinetics of alpha-hydroxymidazolam.
In comparison to water, pretreatment with grapefruit juice did not change the pharmacokinetics or pharmacodynamics of intravenous midazolam. After oral administration, pretreatment with grapefruit juice led to a 56% increase in peak plasma concentration (Cmax), a 79% increase in time to reach Cmax (tmax), and a 52% increase in the area under the plasma concentration-time curve (AUC) of midazolam, which was associated with an increase in the bioavailability from 24% +/- 3% (water) to 35% +/- 3% (Grapefruit juice; mean +/- SEM, p < 0.01) After oral administration of midazolam, pretreatment with grapefruit juice was associated with a 105% increase in tmax and with a 30% increase in the AUC of alpha-hydroxymidazolam. For oral midazolam, pretreatment with grapefruit juice led to significant increases in tmax for all dynamic parameters and in the AUC values for the reaction time and DSST, whereas the maximal dynamic effects remained unchanged.
Pretreatment with grapefruit juice is associated with increased bioavailability and changes in the pharmacodynamics of midazolam that may be clinically important, particularly in patients with other causes for increased midazolam bioavailability such as advanced age, cirrhosis of the liver, and administration of other inhibitors of cytochrome P450.
研究葡萄柚汁对咪达唑仑药代动力学和药效学的影响。
8名健康男性受试者参与了这项开放交叉研究。在用水或葡萄柚汁预处理后，静脉注射（5毫克）或口服（15毫克）咪达唑仑。我们测量了咪达唑仑的药代动力学和药效学（反应时间、数字符号替换测试[DSST]、研究者判断的总体印象以及受试者判断的药物效果）以及α-羟基咪达唑仑的药代动力学。
与水相比，用葡萄柚汁预处理未改变静脉注射咪达唑仑的药代动力学或药效学。口服给药后，用葡萄柚汁预处理导致咪达唑仑的血浆峰浓度（Cmax）增加56%，达峰时间（tmax）增加79%，血浆浓度-时间曲线下面积（AUC）增加52%，这与生物利用度从24%±3%（水）增加到35%±3%（葡萄柚汁；均值±标准误，p<0.01）相关。口服咪达唑仑后，用葡萄柚汁预处理与tmax增加105%以及α-羟基咪达唑仑的AUC增加30%相关。对于口服咪达唑仑，用葡萄柚汁预处理导致所有动态参数的tmax以及反应时间和DSST的AUC值显著增加，而最大动态效应保持不变。
用葡萄柚汁预处理与咪达唑仑生物利用度增加以及药效学变化相关，这可能具有临床重要性，特别是在有其他导致咪达唑仑生物利用度增加原因的患者中，如高龄、肝硬化以及使用其他细胞色素P450抑制剂。
