Effects of alcohol on human carboxylesterase drug metabolism.
Effects of alcohol on human carboxylesterase drug metabolism.
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DOI：
10.1007/s40262-014-0226-2
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发表时间：
2015-06
影响因子：
4.5
通讯作者：
Laizure, S. Casey
中科院分区：
文献类型：
--
作者：
Parker, Robert B.;Hu, Zhe-Yi;Meibohm, Bernd;Laizure, S. Casey
人羧酸酯酶-1 (CES1) 和人羧酸酯酶-2 (CES2) 在许多药物的代谢中发挥着重要作用。酒精是这些酶的已知抑制剂，但对 CES1 和 CES2 的相对影响尚不清楚。本研究的目的是确定酒精对 CES1（奥司他韦）和 CES2（阿司匹林）特定探针代谢的影响。使用重组人羧酸酯酶在体外测定酒精对 CES1 和 CES2 介导的探针药物水解的影响。为了表征酒精的体内作用，健康志愿者单独接受每种探针药物以及与酒精联合使用，然后采集血样并测定奥司他韦、阿司匹林和各自代谢物的药代动力学。酒精在体外显着抑制CES1对奥司他韦的水解，但不影响CES2对阿司匹林的代谢。酒精使奥司他韦0-6小时血浆浓度-时间曲线下面积（AUC）增加27%（范围11-46%，p=0.011），并使代谢物/奥司他韦AUC 0-6小时比率降低34%（范围25-41%，p<0.001）。阿司匹林的药代动力学不受酒精影响。在体外和人体中，酒精均显着抑制CES1对奥司他韦的水解，但不影响CES2对阿司匹林水解为水杨酸。这些结果表明，酒精对 CES1 的抑制可能会导致与其他 CES1 底物药物产生临床上显着的药物相互作用，但不太可能显着影响 CES2 底物药物的水解。
Human carboxylesterase-1 (CES1) and human carboxylesterase-2 (CES2) play an important role in metabolizing many medications. Alcohol is a known inhibitor of these enzymes but the relative effect on CES1 and CES2 is unknown. The aim of this study is to determine the impact of alcohol on the metabolism of specific probes for CES1 (oseltamivir) and CES2 (aspirin). The effect of alcohol on CES1- and CES2-mediated probe drug hydrolysis was determined in vitro using recombinant human carboxylesterase. To characterize the in vivo effects of alcohol, healthy volunteers received each probe drug alone and in combination with alcohol followed by blood sample collection and determination of oseltamivir, aspirin, and respective metabolite pharmacokinetics. Alcohol significantly inhibited oseltamivir hydrolysis by CES1 in vitro but did not affect aspirin metabolism by CES2. Alcohol increased the oseltamivir area under the plasma concentration-time curve (AUC) from 0-6 h by 27% (range 11-46%, p=0.011) and decreased the metabolite/oseltamivir AUC 0-6 h ratio by 34% (range 25-41%, p<0.001). Aspirin pharmacokinetics were not affected by alcohol. Alcohol significantly inhibited the hydrolysis of oseltamivir by CES1 both in vitro and in humans, but did not affect the hydrolysis of aspirin to salicylic acid by CES2. These results suggest that alcohol's inhibition of CES1 could potentially result in clinically significant drug interactions with other CES1-substrate drugs, but it is unlikely to significantly affect CES2-substrate drug hydrolysis.
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影响因子：
4.9
作者：
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通讯作者：
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作者：
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