Abstract
Human carboxylesterase (CES) 1A is responsible for the biotransformation of angiotensin-converting enzyme (ACE) inhibitors such as imidapril and temocapril. Because antidiabetic or antihyperlipidemic drugs are often coadministered with ACE inhibitors in clinical pharmacotherapy, the inhibitory effect of these drugs on CES1A1 enzyme activity was investigated. In addition, the inhibitory effect on CES2 enzyme activity was evaluated to compare it with that on CES1A1. The inhibitory effects were evaluated with 11 antidiabetic and 12 antihyperlipidemic drugs. The imidapril hydrolase activity by recombinant CES1A1 was substantially inhibited by lactone ring-containing statins such as simvastatin and lovastatin and thiazolidinediones such as troglitazone and rosiglitazone. The activity in human liver microsomes was also strongly inhibited by simvastatin and troglitazone (Ki = 0.8 ± 0.1 and 5.6 ± 0.2 μM, respectively). However, statins containing no lactone ring such as pravastatin and fluvastatin did not show strong inhibition. 7-Ethyl-10-[4-(1-piperidono)-1-piperidono]carbonyloxycamptothecin hydrolase activity by recombinant human CES2 was substantially inhibited by fenofibrate (Ki = 0.04 ± 0.01 μM) as well as by simvastatin (0.67 ± 0.09 μM). Other fibrates such as clinofibrate and bezafibrate did not show strong inhibition. Thus, the inhibitory effects of the thiazolidinediones and fenofibrate on CES1A1 and CES2 were different. Some statins such as simvastatin and lovastatin, thiazolidinediones, and fenofibrate might attenuate the drug efficacy of prodrugs biotransformed by CES1A and CES2.
Footnotes
This study was supported by the Japan Society for the Promotion of Science [Grant-in-Aid for Young Scientists (B) 21790418].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.034454.
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The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- CES
- carboxylesterase
- ACE
- angiotensin-converting enzyme
- CPT-11
- 7-ethyl-10-[4-(1-piperidono)-1-piperidono]carbonyloxycamptothecin
- SN-38
- 7-ethyl-10-hydroxycamptothecin
- HLM
- human liver microsomes
- HJM
- human jejunum microsomes
- DMSO
- dimethyl sulfoxide.
- Received May 13, 2010.
- Accepted August 31, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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