Hukkanen Janne, Jacob Peyton, Benowitz Neal L
Division of Clinical Pharmacology and Experimental Therapeutics, Medical Service, San Francisco General Hospital Medical Center, and Department of Medicine, University of California, San Francisco 94143-1220, USA.
Clin Pharmacol Ther. 2006 Nov;80(5):522-30. doi: 10.1016/j.clpt.2006.08.006.
Grapefruit juice is an inhibitor of the cytochrome P450 (CYP) 3A4 enzyme and transporters such as P-glycoprotein and organic anion transporting polypeptides, leading to clinically important interactions. Our objective was to study the effect of grapefruit juice on the pharmacokinetics of nicotine, which is primarily metabolized by the CYP2A6 enzyme.
Ten volunteers were given a 2-mg oral dose of deuterium-labeled nicotine on 3 occasions together with 1 L of water, full-strength grapefruit juice, or half-strength grapefruit juice. Concentrations of nicotine and its metabolites were analyzed in plasma and urine for 8 hours.
Grapefruit juice inhibited the formation of cotinine from nicotine (area under the plasma cotinine concentration-time curve from 0 to 8 hours of 6807 min.ng/mL, 7805 min.ng/mL, and 8007 min.ng/mL for full-strength grapefruit juice, half-strength grapefruit juice, and water, respectively; repeated-measures ANOVA, P=.009). The time to peak plasma concentration of cotinine was delayed (216 minutes, 159 minutes, and 147 minutes, respectively; ANOVA, P=.011), and the peak plasma concentration was lower with grapefruit juice compared with water (18 ng/mL, 21 ng/mL, and 22 ng/mL, respectively; ANOVA, P=.010). Oral clearance, peak plasma concentration, and time to peak plasma concentration of nicotine were not affected. Grapefruit juice increased the renal clearance of nicotine (231 mL/min, 219 mL/min, and 123 mL/min, respectively; ANOVA, P=.045) and cotinine (19 mL/min, 14 mL/min, and 16 mL/min, respectively; ANOVA, P=.002).
Grapefruit juice inhibits the metabolism of nicotine to cotinine, a pathway mediated by CYP2A6, and increases the renal clearance of nicotine and cotinine. Nicotine oral clearance is not affected by grapefruit juice because the inhibition of hepatic metabolism is offset by the increase in the renal clearance of nicotine. However, other compounds metabolized by CYP2A6, as well as other drugs excreted via renal clearance mechanisms similar to those of nicotine, may be susceptible to significant pharmacokinetic grapefruit juice interactions.
葡萄柚汁是细胞色素P450（CYP）3A4酶以及P-糖蛋白和有机阴离子转运多肽等转运蛋白的抑制剂，会导致具有临床重要意义的相互作用。我们的目的是研究葡萄柚汁对主要由CYP2A6酶代谢的尼古丁药代动力学的影响。
10名志愿者分3次口服2毫克氘标记的尼古丁，同时分别饮用1升水、纯葡萄柚汁或半浓度葡萄柚汁。在8小时内分析血浆和尿液中尼古丁及其代谢物的浓度。
葡萄柚汁抑制了尼古丁向可替宁的形成（0至8小时血浆可替宁浓度-时间曲线下面积，纯葡萄柚汁为6807分钟·纳克/毫升，半浓度葡萄柚汁为7805分钟·纳克/毫升，水为8007分钟·纳克/毫升；重复测量方差分析，P = 0.009）。可替宁的血浆峰浓度出现时间延迟（分别为216分钟、159分钟和147分钟；方差分析，P = 0.011），与水相比，葡萄柚汁组的血浆峰浓度更低（分别为18纳克/毫升、21纳克/毫升和22纳克/毫升；方差分析，P = 0.010）。尼古丁的口服清除率、血浆峰浓度和血浆峰浓度出现时间未受影响。葡萄柚汁增加了尼古丁的肾清除率（分别为231毫升/分钟、219毫升/分钟和123毫升/分钟；方差分析，P = 0.045）以及可替宁的肾清除率（分别为19毫升/分钟、14毫升/分钟和16毫升/分钟；方差分析，P = 0.002）。
葡萄柚汁抑制尼古丁代谢为可替宁这一由CYP2A6介导的途径，并增加尼古丁和可替宁的肾清除率。葡萄柚汁不影响尼古丁的口服清除率，因为肝脏代谢的抑制被尼古丁肾清除率的增加所抵消。然而，其他由CYP2A6代谢的化合物，以及其他通过与尼古丁类似的肾清除机制排泄的药物，可能容易受到葡萄柚汁显著的药代动力学相互作用的影响。
