AIMS:Case reports suggest an interaction between rofecoxib and the CYP1A2 substrate tizanidine. Our objectives were to explore the extent and mechanism of this possible interaction and to determine the CYP1A2 inhibitory potency of rofecoxib. METHODS:In a randomized, double-blind, two-phase cross-over study, nine healthy subjects took 25 mg rofecoxib or placebo daily for 4 days and, on day 4, each ingested 4 mg tizanidine. Plasma concentrations and the urinary excretion of tizanidine, its metabolites (M) and rofecoxib, and pharmacodynamic variables were measured up to 24 h. On day 3, a caffeine test was performed to estimate CYP1A2 activity. RESULTS:Rofecoxib increased the area under the plasma concentration-time curve (AUC(0-infinity)) of tizanidine by 13.6-fold [95% confidence interval (CI) 8.0, 15.6; P < 0.001), peak plasma concentration (C(max)) by 6.1-fold (4.8, 7.3; P < 0.001) and elimination half-life (t(1/2)) from 1.6 to 3.0 h (P < 0.001). Consequently, rofecoxib markedly increased the blood pressure-lowering and sedative effects of tizanidine (P < 0.05). Rofecoxib increased several fold the tizanidine/M-3 and tizanidine/M-4 ratios in plasma and urine and the tizanidine/M-5, tizanidine/M-9 and tizanidine/M-10 ratios in urine (P < 0.05). In addition, it increased the plasma caffeine/paraxanthine ratio by 2.4-fold (95% CI 1.4, 3.4; P = 0.008) and this ratio correlated with the tizanidine/metabolite ratios. Finally, the AUC(0-25) of rofecoxib correlated with the placebo phase caffeine/paraxanthine ratio (r = 0.80, P = 0.01). CONCLUSIONS:Rofecoxib is a potent inhibitor of CYP1A2 and it greatly increases the plasma concentrations and adverse effects of tizanidine. The findings suggest that rofecoxib itself is also metabolized by CYP1A2, raising concerns about interactions between rofecoxib and other CYP1A2 substrate and inhibitor drugs.

译文

目的:病例报告表明罗非考昔与CYP1A2底物替扎尼定之间存在相互作用。我们的目标是探索这种可能的相互作用的程度和机制,并确定罗非昔布对CYP1A2的抑制作用。
方法:在一项随机,双盲,两阶段交叉研究中,九名健康受试者每天服用25毫克罗非考昔或安慰剂,持续4天,并在第4天,每人摄入4毫克替扎尼定。在长达24小时内测量替扎尼定,其代谢产物(M)和罗非考昔的血浆浓度和尿排泄,以及药效学变量。在第3天,进行了咖啡因测试以评估CYP1A2的活性。
结果:罗非昔布将替扎尼定的血浆浓度-时间曲线下面积(AUC(0-无穷大))增加了13.6倍[95%置信区间(CI)8.0、15.6; P <0.001),峰值血药浓度(C(max))从1.6到3.0 h的6.1倍(4.8,7.3; P <0.001)和消除半衰期(t(1/2))(P <0.001) 。因此,罗非昔布显着增强了替扎尼定的降压和镇静作用(P <0.05)。罗非昔布将血浆和尿液中替扎尼定/ M-3和替扎尼定/ M-4的比例提高了几倍,尿液中替扎尼定/ M-5,替扎尼定/ M-9和替扎尼定/ M-10的比例提高了几倍(P <0.05)。此外,它使血浆咖啡因/对黄嘌呤比率增加了2.4倍(95%CI 1.4、3.4; P = 0.008),并且该比率与替扎尼定/代谢产物比率相关。最后,罗非昔布的AUC(0-25)与安慰剂相咖啡因/对黄嘌呤的比​​例相关(r = 0.80,P = 0.01)。
结论:罗非昔布是一种有效的CYP1A2抑制剂,它大大提高了血浆浓度和替扎尼定的不良反应。研究结果表明罗非考昔本身也被CYP1A2代谢,引起对罗非考昔与其他CYP1A2底物和抑制剂药物之间相互作用的担忧。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录