Denaro C P, Brown C R, Wilson M, Jacob P, Benowitz N L
Department of Medicine, University of California-San Francisco.
Clin Pharmacol Ther. 1990 Sep;48(3):277-85. doi: 10.1038/clpt.1990.150.
Some recent epidemiologic studies have reported a nonlinear dose-response in the relationship between coffee consumption and health risks, such that the risks increase disproportionately to the increase in dose. Assuming caffeine contributes to the adverse health effects of coffee, a possible explanation for the nonlinear dose-response relationship is dose-dependent metabolism of caffeine. We examined the hypothesis that under chronic dosing conditions the metabolism of caffeine is dose-dependent. Nine healthy subjects were given, in randomized 5-day treatment blocks, placebo, 4.2 (low) and 12 (high) mg/kg/day caffeine in decaffeinated coffee, in six divided doses spaced throughout the day. On the third day of each dosing period, 25 mg of stable-isotope labeled caffeine (2-13C, 1,3-15N2) was given intravenously. Clearance of labeled caffeine fell from 0.118 (placebo treatment) to 0.069 (low dose; p less than 0.005) and to 0.54 (high dose; p less than 0.001) L/hr/kg. The formation and metabolite clearances of paraxanthine, the major primary metabolite of caffeine, also decreased comparing the low and high doses (p less than 0.05). We conclude that caffeine metabolism is dose-dependent, resulting in nonlinear accumulation of methylxanthines in the body. Dose-dependent metabolism of caffeine may explain in part why people who drink large amounts of coffee are at greater risk for cardiovascular disease.
最近一些流行病学研究报告称，咖啡摄入量与健康风险之间存在非线性剂量反应关系，即风险增加幅度与剂量增加不成比例。假设咖啡因是咖啡对健康产生不良影响的原因，那么这种非线性剂量反应关系的一个可能解释是咖啡因的剂量依赖性代谢。我们检验了在长期给药条件下咖啡因代谢具有剂量依赖性这一假设。9名健康受试者被随机分配到5天的治疗组，分别服用脱咖啡因咖啡中的安慰剂、4.2（低剂量）和12（高剂量）毫克/千克/天的咖啡因，分6次全天给药。在每个给药期的第三天，静脉注射25毫克稳定同位素标记的咖啡因（2-13C，1,3-15N2）。标记咖啡因的清除率从0.118（安慰剂治疗）降至0.069（低剂量；p<0.005）和0.054（高剂量；p<0.001）升/小时/千克。咖啡因的主要初级代谢产物副黄嘌呤的生成和代谢产物清除率在低剂量和高剂量之间也有所下降（p<0.05）。我们得出结论，咖啡因代谢具有剂量依赖性，导致甲基黄嘌呤在体内非线性蓄积。咖啡因的剂量依赖性代谢可能部分解释了为什么大量饮用咖啡的人患心血管疾病的风险更高。
