Shi J, Benowitz N L, Denaro C P, Sheiner L B
Division of Clinical Pharmacology and Experimental Therapeutics, San Francisco General Hospital Medical Center, California 94110.
Clin Pharmacol Ther. 1993 Jan;53(1):6-14. doi: 10.1038/clpt.1993.3.
We propose a parametric pharmacokinetic-pharmacodynamic model for caffeine that quantifies the development of tolerance to the pressor effect of the drug and characterizes the mean behavior and inter-individual variation of both pharmacokinetics and pressor effect. Our study in a small group of subjects indicates that acute tolerance develops to the pressor effect of caffeine and that both the pressor effect and tolerance occur after some time delay relative to changes in plasma caffeine concentration. The half-life of equilibration of effect with plasma caffeine concentration is about 20 minutes. The half-life of development and regression of tolerance is estimated to be about 1 hour, and the model suggests that tolerance, at its fullest, causes more than a 90% reduction of initial (nontolerant) effect. Whereas tolerance to the pressor effect of caffeine develops in habitual coffee drinkers, the pressor response is regained after relatively brief periods of abstinence. Because of the rapid development and regression of tolerance, the pressor response to caffeine depends on how much caffeine is consumed, the schedule of consumption, and the elimination half-life of caffeine.
我们提出了一种针对咖啡因的参数化药代动力学-药效学模型，该模型量化了对药物升压作用耐受性的发展，并描述了药代动力学和升压作用的平均行为及个体间差异。我们在一小群受试者中的研究表明，对咖啡因的升压作用会产生急性耐受性，且相对于血浆咖啡因浓度的变化，升压作用和耐受性均会在一段时间延迟后出现。效应与血浆咖啡因浓度达到平衡的半衰期约为20分钟。耐受性发展和消退的半衰期估计约为1小时，该模型表明，耐受性充分发展时会使初始（非耐受性）效应降低超过90%。虽然习惯性咖啡饮用者会对咖啡因的升压作用产生耐受性，但在相对短暂的 abstinence 期后，升压反应会恢复。由于耐受性发展和消退迅速，对咖啡因的升压反应取决于摄入的咖啡因量、摄入时间表以及咖啡因的消除半衰期。
