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Esterase phenotyping in human liver in vitro: specificity of carboxylesterase inhibitors

Umehara, Ken-Ichi, Zollinger, Markus, Kigondu, Elizabeth, Witschi, Marc, Juif, Claire, Huth, Felix, Schiller, Hilmar, Chibale, Kelly and Camenisch, Gian P. (2016) Esterase phenotyping in human liver in vitro: specificity of carboxylesterase inhibitors. Xenobiotica. pp. 1-6. ISSN 0049-82541366-5928


Esterases may play a major role in the pre-systemic or systemic clearance of drugs with functional groups amenable to hydrolysis, particularly in case of ester prodrugs. To understand the processes involved in the elimination of such drugs and to predict potential drug-drug interactions, it is necessary to determine the involved esterases in in vitro experiments (enzyme phenotyping). However, the tools currently available for this purpose are relatively scarce. The work presented in this communication aimed at determining the selectivity of known esterase inhibitors for carboxylesterases 1 and 2 (CES1 and CES2) in the human liver to clarify their suitability for esterase phenotyping. The main result was that eserine, when used at concentrations around 10 µM, is a highly specific CES2 inhibitor (besides being an inhibitor of cholinesterases), whereas other esterase inhibitors turned out less selective. When used together with tacrine (inhibitor of cholinesterases but not CES) and EDTA (inhibitor of paraoxonases), the involvement of the main drug hydrolyzing esterases in the clearance of a drug candidate can be elucidated. A second approach to esterase phenotyping, also shortly presented here, is based on data from recombinant (or isolated) esterases, together with relative activity factors, relating their activities to those of the same enzymes in subcellular fractions from the human liver. These two approaches will help to characterize the hydrolytic metabolism of drug candidates in a similar manner as practiced routinely for the oxidative metabolism by cytochrome P450 enzymes.

Item Type: Article
Keywords: Esterase, phenotyping, liver, cholinesterase (ChE), carboxylesterase (CES), arylesterase/paraoxonase (PON)
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45