Backman Janne T, Granfors Marika T, Neuvonen Pertti J
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Eur J Clin Pharmacol. 2006 Jun;62(6):451-61. doi: 10.1007/s00228-006-0127-x. Epub 2006 Apr 27.
Rifampicin greatly reduces the plasma concentrations of many drugs. Our aim was to characterise the inducibility of cytochrome P450 (CYP) 1A2 by rifampicin, using tizanidine and caffeine as probe drugs for presystemic and systemic CYP1A2-mediated metabolism.
In a randomised, 2-phase crossover study, ten healthy volunteers were given a 5-day pretreatment with 600 mg rifampicin or placebo once daily. On day 6, a single 4-mg dose of tizanidine was administered orally. Plasma and urine concentrations of parent tizanidine and several of its metabolites (M-3, M-4, M-5, M-9, M-10) and pharmacodynamic variables were measured up to 24 h. A caffeine test was performed in both phases.
Rifampicin moderately reduced the peak plasma concentration (by 51%; P = 0.002) and area under the plasma concentration-time curve [AUC(0-infinity)] (by 54%; P = 0.009) of parent tizanidine, and had no effect on its half-life. The tizanidine/M-3 and tizanidine/M-4 AUC(0-infinity) ratios were slightly (by 30%; P = 0.014; and by 38%; P = 0.007) decreased by rifampicin. Also, the excretion of metabolites M-3, M-4 and M-5 into urine was reduced (P < 0.005), but that of M-10 was increased (P = 0.008) by rifampicin. Rifampicin reduced the tizanidine/M-10 ratio (by 55%; P = 0.047) but had no significant effect on the other tizanidine/metabolite ratios in urine. The caffeine/paraxanthine ratio was reduced by 23% (P = 0.081) by rifampicin. The effect of rifampicin on the caffeine/paraxanthine ratio correlated significantly with the effect of rifampicin on, for example, the AUC(0-infinity) of tizanidine and the tizanidine/M-3 AUC(0-infinity) ratio. The pharmacodynamic effects of tizanidine were reduced by rifampicin.
Rifampicin moderately decreases the plasma concentrations of tizanidine. The strong inducing effects of rifampicin on other CYP enzymes, e.g. CYP3A4, may have contributed to the findings, and the inducibility of CYP1A2-mediated presystemic (tizanidine) and systemic (tizanidine, caffeine) metabolism by rifampicin is weak at the most. Compared to CYP3A4 substrate drugs, substrates of CYP1A2 are much less susceptible to drug interactions caused by enzyme inducers of the rifampicin type.
利福平可大幅降低多种药物的血浆浓度。我们的目的是通过使用替扎尼定和咖啡因作为肝首过效应和全身CYP1A2介导代谢的探针药物，来表征利福平对细胞色素P450（CYP）1A2的诱导性。
在一项随机、两阶段交叉研究中，10名健康志愿者接受为期5天的预处理，每天一次服用600mg利福平或安慰剂。在第6天，口服单剂量4mg替扎尼定。测量至24小时的替扎尼定母体及其几种代谢物（M-3、M-4、M-5、M-9、M-10）的血浆和尿液浓度以及药效学变量。在两个阶段均进行了咖啡因试验。
利福平适度降低了替扎尼定母体的血浆峰浓度（降低51%；P = 0.002）和血浆浓度-时间曲线下面积[AUC(0-∞)]（降低54%；P = 0.009），且对其半衰期无影响。利福平使替扎尼定/M-3和替扎尼定/M-4的AUC(0-∞)比值略有降低（分别降低30%；P = 0.014；和38%；P = 0.007）。此外，利福平使代谢物M-3、M-4和M-5的尿排泄减少（P < 0.005），但使M-10的尿排泄增加（P = 0.008）。利福平降低了替扎尼定/M-10比值（降低55%；P = 0.047），但对尿液中其他替扎尼定/代谢物比值无显著影响。利福平使咖啡因/副黄嘌呤比值降低23%（P = 0.081）。利福平对咖啡因/副黄嘌呤比值的影响与利福平对替扎尼定AUC(0-∞)以及替扎尼定/M-3 AUC(0-∞)比值等的影响显著相关。利福平降低了替扎尼定的药效学作用。
利福平适度降低替扎尼定的血浆浓度。利福平对其他CYP酶（如CYP3A4）的强诱导作用可能导致了这些结果，并且利福平对CYP1A2介导的肝首过效应（替扎尼定）和全身（替扎尼定、咖啡因）代谢的诱导性至多很弱。与CYP3A4底物药物相比，CYP1A2的底物对利福平类型的酶诱导剂引起的药物相互作用的敏感性要低得多。
