Chemico-Biological Interactions 2013-03-25

Inhibition of human carboxylesterases hCE1 and hiCE by cholinesterase inhibitors.

Lyudmila G Tsurkan, M Jason Hatfield, Carol C Edwards, Janice L Hyatt, Philip M Potter

Index: Chem. Biol. Interact. 203(1) , 226-30, (2013)

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Abstract

Carboxylesterases (CEs) are ubiquitously expressed proteins that are responsible for the detoxification of xenobiotics. They tend to be expressed in tissues likely to be exposed to such agents (e.g., lung and gut epithelia, liver) and can hydrolyze numerous agents, including many clinically used drugs. Due to the considerable structural similarity between cholinesterases (ChE) and CEs, we have assessed the ability of a series of ChE inhibitors to modulate the activity of the human liver (hCE1) and the human intestinal CE (hiCE) isoforms. We observed inhibition of hCE1 and hiCE by carbamate-containing small molecules, including those used for the treatment of Alzheimer's disease. For example, rivastigmine resulted in greater than 95% inhibition of hiCE that was irreversible under the conditions used. Hence, the administration of esterified drugs, in combination with these carbamates, may inadvertently result in decreased hydrolysis of the former, thereby limiting their efficacy. Therefore drug:drug interactions should be carefully evaluated in individuals receiving ChE inhibitors.Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.