Robert B Parker1, Zhe-Yi Hu, Bernd Meibohm, S Casey Laizure. 1. Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Room 346, Memphis, TN, 38163, USA, rparker@uthsc.edu.
Abstract
BACKGROUND AND OBJECTIVE: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 was to determine the impact of alcohol on the metabolism of specific probes for CES1 (oseltamivir) and CES2 (aspirin). METHODS: 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. RESULTS: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 to 6 h (AUC0 → 6 h) by 27% (range 11-46%, p = 0.011) and decreased the metabolite/oseltamivir AUC0 → 6 h ratio by 34% (range 25-41%, p < 0.001). Aspirin pharmacokinetics were not affected by alcohol. CONCLUSIONS: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.
RCT Entities:
BACKGROUND AND OBJECTIVE:Humancarboxylesterase-1 (CES1) and humancarboxylesterase-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 was to determine the impact of alcohol on the metabolism of specific probes for CES1 (oseltamivir) and CES2 (aspirin). METHODS: The effect of alcohol on CES1- and CES2-mediated probe drug hydrolysis was determined in vitro using recombinant humancarboxylesterase. 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. RESULTS: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 to 6 h (AUC0 → 6 h) by 27% (range 11-46%, p = 0.011) and decreased the metabolite/oseltamivir AUC0 → 6 h ratio by 34% (range 25-41%, p < 0.001). Aspirin pharmacokinetics were not affected by alcohol. CONCLUSIONS: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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