Mays D C, Camisa C, Cheney P, Pacula C M, Nawoot S, Gerber N
Department of Pharmacology, Ohio State University, Columbus 43210.
Clin Pharmacol Ther. 1987 Dec;42(6):621-6. doi: 10.1038/clpt.1987.209.
The acute effect of a single oral dose of methoxsalen on the pharmacokinetics of caffeine was investigated in five nonsmoking volunteers with psoriasis. Caffeine, 200 mg orally, was administered to each subject at baseline before treatment with methoxsalen. One week later each subject was given a single oral dose of 1.2 mg/kg methoxsalen 1 hour before administrations of another oral dose of 200 mg caffeine. The clearance of caffeine declined markedly from 110 +/- 17 ml/min (mean +/- SE) in the control study to 34 +/- 5 ml/min after methoxsalen. During the period of maximum inhibition the mean elimination half-life of caffeine increased from 5.6 hours at baseline to 57 hours after administration of methoxsalen. The peak concentration of caffeine and the time to reach the peak concentration of caffeine were not affected by pretreatment with methoxsalen. Thus, methoxsalen, administered acutely, is a potent inhibitor of caffeine metabolism in humans with psoriasis. Results of this investigation suggest that the elimination of concurrently administered drugs may be inhibited in patients receiving methoxsalen. In comparison with other drugs, methoxsalen is the most potent inhibitor of drug metabolism in humans. Other work has shown that inhibition of drug metabolism by methoxsalen is associated with both extensive covalent binding of metabolite(s) of methoxsalen to liver microsomal protein in vitro and in vivo and inactivation of cytochrome P-450.
在5名患有银屑病的非吸烟志愿者中研究了单次口服甲氧沙林对咖啡因药代动力学的急性影响。在使用甲氧沙林治疗前的基线期，给每位受试者口服200毫克咖啡因。一周后，在再次口服200毫克咖啡因前1小时，给每位受试者单次口服1.2毫克/千克甲氧沙林。咖啡因的清除率从对照研究中的110±17毫升/分钟（平均值±标准误）显著下降至甲氧沙林给药后的34±5毫升/分钟。在最大抑制期，咖啡因的平均消除半衰期从基线时的5.6小时增加至甲氧沙林给药后的57小时。咖啡因的峰值浓度及达到咖啡因峰值浓度的时间不受甲氧沙林预处理的影响。因此，急性给予甲氧沙林对患有银屑病的人类而言是咖啡因代谢的强效抑制剂。本研究结果提示，接受甲氧沙林治疗的患者可能会出现同时服用药物的消除受到抑制的情况。与其他药物相比，甲氧沙林是人类中最有效的药物代谢抑制剂。其他研究表明，甲氧沙林对药物代谢的抑制作用与甲氧沙林代谢物在体外和体内与肝微粒体蛋白的广泛共价结合以及细胞色素P-450的失活有关。
