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Xenobiotica
the fate of foreign compounds in biological systems
Volume 46, 2016 - Issue 10
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General Xenobiochemistry

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

, , , , , , , & show all
Pages 862-867 | Received 21 Oct 2015, Accepted 15 Dec 2015, Published online: 18 Feb 2016
 

Abstract

1. Esterases may play a major role in the clearance of drugs with functional groups amenable to hydrolysis, particularly in the case of ester prodrugs. To understand the processes involved in the elimination of such drugs, it is necessary to determine the esterases involved. However, the tools currently available for this enzyme phenotyping are relatively scarce.

2. The work was aimed at summarizing the selectivity of esterase inhibitors for carboxylesterases 1 and 2 (CES1 and CES2) in the human liver to clarify their suitability for esterase phenotyping. Eserine, at around 10 μM, was found to be a highly specific CES2 inhibitor, whereas other esterase inhibitors turned out less selective. When used together with tacrine, which inhibits cholinesterases but not CES, and ethylenediaminetetraacetic acid (inhibitor of paraoxonases), the involvement of the hydrolyzing esterases in the hepatic clearance of a drug can be elucidated.

3. The second approach to esterase phenotyping is based on data from recombinant or isolated esterases, together with relative activity factors, which relate their activities to those of the same enzymes in subcellular fractions.

4. 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.

Acknowledgements

South African Medical Research Council and South African Research Chairs Initiative of the Department of Science and Technology administered through the South African National Research Foundation are gratefully acknowledged for support.

Declaration of interest

The authors report no conflicts of interest.

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