Natural Products as Modulators of CES1 Activity.Drug Metab Dispos. 2020 Jun 26 [Online ahead of print]DM
Carboxylesterase 1 (CES1) is the predominant esterase expressed in the human liver and capable of catalyzing the hydrolysis of a wide range of therapeutic agents, toxins, and endogenous compounds. Accumulating studies have demonstrated associations between the expression and activity of CES1 and the pharmacokinetics and/or pharmacodynamics of CES1 substrate medications (e.g. methylphenidate, clopidogrel, oseltamivir). Therefore, any perturbation of CES1 by co-ingested xenobiotics could potentially compromise treatment'. Natural products are known to alter drug disposition by modulating cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) enzymes, but this issue is less thoroughly explored with CES1. We report the results of a systematical literature search and discuss natural products as potential modulators of CES1 activity. The majority of research reports reviewed were in vitro investigations which require further confirmation through clinical study. Cannabis products (Δ⁹-tetrahydrocannabinol, cannabidiol, cannabinol), supplements from various plant sources containing naringenin, quercetin, luteolin, oleanolic acid, and asiatic acid, and certain traditional medicines (Danshen and Zhizhuwan) appear to pose the highest inhibition potential. In addition, ursolic acid, gambogic acid, and glycyrrhetic acid, if delivered intravenously, may attain high enough systemic concentrations to significantly inhibit CES1. The provision of a translational interpretation of in vitro assessments of natural product actions and interactions is limited by the dearth of basic pharmacokinetic data of the natural compounds exhibiting potent in vitro influences on CES1 activity. This is a major impediment to assigning even potential clinical significance. The modulatory effects on CES1 expression after chronic exposure to natural products warrants further investigation.