Reversible Inhibition of Human Carboxylesterases by Acyl Glucuronides

Abstract

Carboxylesterases hydrolyze esters, amides, and thioesters to produce carboxylic acids and resulting alcohols, amines, and thiols, respectively. Uridine 59-diphosphate-glucuronosyltransferases are colocalized with carboxylesterases and have the potential to further metabolize carboxylic acids to acyl glucuronides, but it is currently unknown if acyl glucuronides, being esters, also interact with carboxylesterases. Objective: This study explores the ability of acyl glucuronides to act as substrates or inhibitors of human carboxylesterases 1 (hCES1) and 2 (hCES2). Methods: The stability of six acyl glucuronides in the presence of hCES1, hCES2, and buffer alone (100 mM potassium phosphate, pH 7.4, 37°C) were investigated. Reversible inhibition of 4-nitrophenyl acetate hydrolysis by the acyl glucuronides was also studied. Diclofenac-b-D-glucuronide was used to explore potential time-dependent inactivation. Lastly, both hCES1 and hCES2 were shown not to catalyze the hydrolysis of the acyl glucuronides studied. Conclusion: Drug-drug interaction studies may be warranted for drugs that metabolize to acyl glucuronides due to the potential inhibition of hCESs.

Metabolite profiling of carbamazepine and ibuprofen in Solea senegalensis bile using high-resolution mass spectrometry

“…As an elevation of CYP3A4-mediated BFCOD activity also occurred with IBU (p < 0.05) and CBZ (albeit not significant), while CYP1A-mediated EROD activity was not affected [22], it is plausible that induction of CYP3A4 and CbE may occur by the same mechanism such as via the nuclear receptor PXR as revealed in fish as well as in mammals [11,29]. It could also be hypothesized that the lower response after IBU injection, despite the dose assayed was higher, could be due to the inhibition of CbEs by NSAID glucuronides formed as revealed in humans [30]. To the best of our knowledge, this is the first report on CbE induction by these two pharmaceutical drugs in fish although an induction by other drugs such as gemfibrozil, nonylphenol, and ethinylestradiol was formerly reported in vivo in the same fish species [31].…”