背景:超短效苯二氮卓类药物雷米唑仑,批准用于程序镇静和全身麻醉,被羧酸酯酶1(CES1)灭活。
目的:研究了雷马唑仑参与CES1介导的药物-药物相互作用(DDIs)。
方法:在与11种不同药物的共同暴露实验中,研究了雷米唑仑可能的相互作用。Further,CES1的底物和抑制剂,在文献中鉴定,使用药代动力学和Ki或IC50值评估可能的体内抑制作用。仅具有一种公开的抑制浓度的化合物和缺乏抑制数据的CES1底物被指定为保守的Ki值。
结果:在人类肝脏匀浆和/或血细胞中,利马唑仑对艾司洛尔和兰地洛尔的代谢无明显抑制作用,which,反过来,在高达98和169μM时,分别,没有抑制人肝匀浆中瑞咪唑安定的水解。在人的肝脏S9部分,IC50值范围为0.69μM(辛伐他汀)和57μM(地尔硫卓)至>100μM(阿托伐他汀),对于剩余的测试项目(安非他酮,卡维地洛,奈非那韦,尼群地平,和替米沙坦),它们的范围从126到658μM。瑞芬太尼即使在1250μM时也无效。符合指南的评估显示,通过CES1与雷米马唑仑没有相关的药物相互作用。基于算法的预测与人类研究数据一致。在文献中确定的CES1抑制剂和底物中,只有氨苯砜和rufinamide被发现是可能的体内抑制剂的雷马唑仑代谢。
结论:数据和分析表明,雷米咪唑安定用于CES1介导的药代动力学DDI的潜力非常低。理论方法和编制的数据不是雷米唑仑特有的,因此,适用于其他CES1基材的评估。
BACKGROUND: The ultra-short-acting benzodiazepine
remimazolam, approved for procedural sedation and general anesthesia, is inactivated by carboxylesterase 1 (CES1).
OBJECTIVE: Remimazolam´s involvement in CES1-mediated drug-drug interactions (DDIs) was investigated.
METHODS: Possible interactions of
remimazolam were studied in co-exposure experiments with eleven different drugs. Further, substrates and inhibitors of CES1, identified in the literature, were evaluated for possible in-vivo inhibition using pharmacokinetic and Ki or IC50 values. Compounds with only one published inhibitory concentration and CES1 substrates lacking inhibition data were assigned conservative Ki values.
RESULTS: In human liver homogenates and/or blood cells,
remimazolam showed no significant inhibition of esmolol and landiolol metabolism, which, in turn, at up to 98 and 169 μM, respectively, did not inhibit remimazolam hydrolysis by human liver homogenates. In human liver S9 fractions, IC50 values ranged from 0.69 μM (simvastatin) and 57 μM (diltiazem) to > 100 μM (atorvastatin) and, for the remaining test items (bupropion, carvedilol, nelfinavir, nitrendipine, and telmisartan), they ranged from 126 to 658 μM. Remifentanil was ineffective even at 1250 μM. Guidance-conforming evaluation revealed no relevant drug-drug interactions with
remimazolam via CES1. The algorithm-based predictions were consistent with human study data. Among CES1 inhibitors and substrates identified in the literature, only dapsone and rufinamide were found to be possible in-vivo inhibitors of remimazolam metabolism.
CONCLUSIONS: Data and analyses suggest a very low potential of remimazolam for pharmacokinetic DDIs mediated by CES1. The theoretical approach and compiled data are not specific to
remimazolam and, hence, applicable in the evaluation of other CES1 substrates.