RT Journal Article SR Electronic T1 Different Inhibitory Effects in Rat and Human Carboxylesterases JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 956 OP 961 DO 10.1124/dmd.108.024331 VO 37 IS 5 A1 Shiori Takahashi A1 Miki Katoh A1 Takashi Saitoh A1 Miki Nakajima A1 Tsuyoshi Yokoi YR 2009 UL http://dmd.aspetjournals.org/content/37/5/956.abstract AB In vitro inhibition studies on drug-metabolizing enzyme activity are useful for understanding drug-drug interactions and for drug development. However, the profile of the inhibitory effects of carboxylesterase (CES) activity has not been fully investigated concerning species and tissue differences. In the present study, we measured the inhibitory effects of 15 drugs and 1 compound on CES activity using liver and jejunum microsomes and cytosol in human and rat. In addition, the inhibition constant (Ki values) and patterns were determined for the compounds exhibiting strong inhibition. Hydrolysis of imidapril and irinotecan hydrochloride (CPT-11) is catalyzed mainly by CES1 and CES2, respectively. In the inhibition study, imidaprilat formation from imidapril in human liver was strongly inhibited by nordihydroguaiaretic acid (NDGA) and procainamide. The inhibition profile and pattern were similar in human liver and rat liver. The compounds showing potent inhibition were similar between liver and jejunum. The Ki value of NDGA (Ki = 13.3 ± 1.5 μM) in human liver microsomes was 30-fold higher than that in rat liver microsomes (Ki = 0.4 ± 0.0 μM). On the other hand, 7-ethyl-10-hydroxycamptothecin (SN-38) formation from CPT-11 was not inhibited except by carvedilol, manidipine, and physostigmine. The Ki value of physostigmine (Ki = 0.3 ± 0.0 μM) in human jejunum cytosol was 10-fold lower than that in rat jejunum cytosol (Ki = 3.1 ± 0.4 μM) and was similar to that for manidipine. The present study clarified the species differences in CES inhibition. These results are useful for the development of prodrugs. The American Society for Pharmacology and Experimental Therapeutics