Different inhibitory effects in rat and human carboxylesterases.

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 (K(i) 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 K(i) value of NDGA (K(i) = 13.3 +/- 1.5 microM) in human liver microsomes was 30-fold higher than that in rat liver microsomes (K(i) = 0.4 +/- 0.0 microM). On the other hand, 7-ethyl-10-hydroxycamptothecin (SN-38) formation from CPT-11 was not inhibited except by carvedilol, manidipine, and physostigmine. The K(i) value of physostigmine (K(i) = 0.3 +/- 0.0 microM) in human jejunum cytosol was 10-fold lower than that in rat jejunum cytosol (K(i) = 3.1 +/- 0.4 microM) 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.