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Mammalian carboxylesterases (CES), the key members of the serine hydrolase superfamily, hydrolyze a wide range of endogenous substances and xenobiotics bearing ester or amide bond(s). In humans, most of identified CES are segregated into the CES1A and CES2A subfamilies. Strong inhibition on human CES (including hCES1A and hCES2A) may modulate pharmacokinetic profiles of CES-substrate drugs, thereby changing the pharmacological and toxicological responses of these drugs. This review covered recent advances in discovery of hCES inhibitors from clinically available medications, as well as their impact on CES-associated drug metabolism. Three comprehensive lists of hCES inhibitors deriving from clinically available medications including therapeutic drugs, pharmaceutical excipients and herbal medicines, alongside with their inhibition potentials and inhibition parameters, are summarized. Furthermore, the potential risks of hCES inhibitors to trigger drug/herb-drug interactions (DDIs/HDIs) and future concerns in this field are highlighted. Potent hCES inhibitors may trigger clinically relevant DDIs/HDIs, especially when these inhibitors are co-administrated with CES substrate-drugs with very narrow therapeutic windows. All data and knowledge presented here provide key information for the clinicians to assess the risks of clinically available hCES inhibitors on drug metabolism. In future, more practical and highly specific substrates for hCES1A/hCES2A should be developed and used for studies on CES-mediated DDIs/HDIs both in vitro and in vivo., (Copyright © 2021 Elsevier B.V. All rights reserved.)

We investigated the inhibitory effects of 13 organophosphate esters (OPEs) and hydrolytic metabolites on the carboxylesterase activity of rat liver microsomes in vitro in order to examine whether there might be a potential impact on human health, and to elucidate the structure activity relationship. Among the test compounds, 2-ethylhexyl diphenyl phosphate (EDPhP) was the most potent inhibitor of carboxylesterase activity, as measured in terms of 4-nitrophenol acetate hydrolase activity, followed by tri-m-cresyl phosphate (TmCP), cresyl diphenyl phosphate (CDPhP) and triphenyl phosphate (TPhP). The IC 50 values were as follows: EDPhP (IC 50 : 0.03 μM) > TmCP (0.4 μM) > CDPhP (0.8 μM) > TPhP (14 μM) > tris(1,3-dichloro-2-propyl) phosphate (17 μM) > tris(2-ethylhexyl) phosphate (77 μM) > tri-n-propyl phosphate (84 μM) > tris(2-chloroethyl) phosphate (104 μM) > tris(2-butoxyethyl) phosphate (124 μM) > tri-n-butyl phosphate (230 μM). The IC 50 value of EDPhP was three orders of magnitude lower than that of bis(4-nitrophenyl) phosphate, which is widely used as an inhibitor of carboxylesterase. Trimethyl phosphate, triethyl phosphate and tris(2-chloroisopropyl) phosphate slightly inhibited the carboxylesterase activity; their IC 50 values were above 300 μM. Lineweaver-Burk plots indicated that the inhibition by several OPEs was non-competitive. Diphenyl and monophenyl phosphates, which are metabolites of TPhP, showed weaker inhibitory effects than that of TPhP., (Copyright © 2020 Elsevier B.V. All rights reserved.)

We have recently synthesized a series of phosphorylated flavonoids and identified some of them as potent inhibitors of pancreatic cholesterol esterase (CEase) with excellent selectivity for CEase over acetylcholinesterase (AChE). In the present paper, we investigated the inhibitory activities of these compounds against porcine liver carboxylesterase (CE) since carboxylesterases (CEs) are another family of serine esterases responsible for the metabolism and detoxification of many ester-containing xenobiotics and clinical esterified drugs, and there exists much structural similarity between CEase and CEs. The results indicated that phosphorylated flavonoids exhibited significantly improved inhibition potency toward CE than their parent compounds, and six of them had IC50 values less than 5.0nM. Among all compounds tested, compounds 3d and 3e are the two most potent inhibitors of CE, giving IC50 values of 1.79nM and 1.58nM, respectively. Interestingly, these compounds inhibited CEase and CE with similar structure activity correlations, and those with high inhibitory activities toward CEase could also inhibit CE efficiently. The presences of a free hydroxyl group at position 5 and a phosphate group at position 7 of the phosphorylated flavonoids are favorable to the inhibition of CE. The inhibition mechanism and kinetic characterization studies of the most potent inhibitors revealed that they are irreversible competitive inhibitors., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

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.)

An endemic North African Saharan plant from of the Apiaceae family, Deverra scoparia, used locally for medicinal preparations, showed a strong inhibitory effect on porcine liver carboxylesterase. The active compound from the aerial part of the plant was purified by semi-preparative HPLC and photodiode array detection, and structurally determined by (1)H, (13)C NMR and mass spectroscopy methods. This compound was identified as flavone-3,4',7-trihydroxy-3'-methoxy-7-glucoside and it was found to be a powerful competitive inhibitor of porcine liver carboxylesterase with a inhibition constant value of 16 microM. Based on the structural features of the inhibitor and the enzyme active site region, it seems that the flavonoside binds to the surface of the enzyme. The low K(i) value suggests some physiological significance of such inhibitory activity, especially concerning the bio-transformation of xenobiotics.