Rifampicin is only a weak inducer of CYP1A2-mediated presystemic and systemic metabolism: studies with tizanidine and caffeine
Rifampicin is only a weak inducer of CYP1A2-mediated presystemic and systemic metabolism: studies with tizanidine and caffeine
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DOI：
10.1007/s00228-006-0127-x
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发表时间：
2006-06-01
影响因子：
2.9
通讯作者：
Neuvonen, PJ
中科院分区：
文献类型：
--
作者：
Backman, JT;Granfors, MT;Neuvonen, PJ
目的：利福平可显著降低多种药物的血药浓度。我们的目的是以替扎尼定和咖啡因为探针药物，研究利福平对细胞色素P450(CyP1A2)1A2的诱导作用。方法：在一项随机的两阶段交叉研究中，10名健康志愿者接受了为期5天的利福平或安慰剂每日一次的预治疗。在第6天，单次口服4 mg的替扎尼定。测定母体替扎尼定及其几种代谢物(M-3、M-4、M-5、M-9、M-10)的血药浓度、尿药浓度及药效学参数。结果：利福平可适度降低替扎尼定的血药浓度(降低51%；P=0.002)和血药浓度-时间曲线下面积[AUC(0-无穷大)](54%；P=0.009)，对其半衰期无影响。利福平使替扎尼定/M-3和替扎尼定/M-4AUC(0-无穷大)略有下降(分别下降30%和38%，P=0.014和P=0.007)。利福平还能减少代谢产物M-3、M-4和M-5的排泄(P<；0.005)，增加M-10的排泄(P=0.008)。利福平使替扎尼定/M-10比值降低(55%；P=0.047)，但对尿替扎尼定/代谢物比值无明显影响。利福平使咖啡因/对黄嘌呤比值降低23%(P=0.081)。利福平对咖啡因/对黄嘌呤比值的影响与利福平对替扎尼定的AUC(0-无穷大)和替扎尼定/M-3AUC(0-无穷大)的影响显著相关。利福平可降低替扎尼定的药效学效应。结论：利福平可适度降低替扎尼定的血药浓度。利福平对CYP3A4等其他CYP酶的强烈诱导作用可能是导致这一结果的原因之一，而利福平对CYP1A2介导的收缩前期(替扎尼定)和全身代谢(替扎尼定、咖啡因)的诱导作用最弱。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。
Objective: 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. Methods: 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. Results: 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. Conclusion: 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.