Appel DI

References (4)

Title : Prediction and in vitro evaluation of selected protease inhibitor antiviral drugs as inhibitors of carboxylesterase 1: a potential source of drug-drug interactions - Rhoades_2012_Pharm.Res_29_972
Author(s) : Rhoades JA , Peterson YK , Zhu HJ , Appel DI , Peloquin CA , Markowitz JS
Ref : Pharm Res , 29 :972 , 2012
Abstract : PURPOSE: To predict and determine whether the protease inhibitors (PIs) nelfinavir, amprenavir, atazanavir, ritonavir, and saquinavir could serve as metabolic inhibitors of the human CES1 (hCES1) using both molecular modeling techniques and in vitro inhibition assays. METHODS: Initially, a molecular modeling approach was utilized to predict whether the selected PIs could serve as hCES1 inhibitors. The inhibitory effects of these PIs on hCES1 activity were then further evaluated utilizing previously established in vitro assay. RESULTS: Pharmacophore and 2D-QSAR modeling predicted that nelfinavir would serve as a potent hCES1 inhibitor. This hypothesis was validated by in vitro hCES1 inhibition studies. Other PIs (amprenavir, atazanavir, ritonavir, saquinavir) were evaluated and also shown to be hCES1 inhibitors in vitro, although substantially less potent relative to nelfinavir. CONCLUSION: Computational molecular modeling is a valid approach to identify potential hCES1 inhibitors as candidates for further assessment using validated in vitro techniques. DDIs could occur when nelfinavir is co-administered with drugs metabolized by hCES1.
ESTHER : Rhoades_2012_Pharm.Res_29_972
PubMedSearch : Rhoades_2012_Pharm.Res_29_972
PubMedID: 22161308

Title : Identification of selected therapeutic agents as inhibitors of carboxylesterase 1: potential sources of metabolic drug interactions - Zhu_2010_Toxicology_270_59
Author(s) : Zhu HJ , Appel DI , Peterson YK , Wang Z , Markowitz JS
Ref : Toxicology , 270 :59 , 2010
Abstract : A series of studies were designed and carried out in order to explore the potential for the major human hepatic hydrolase, carboxylesterase 1 (hCES1), to serve as a target of metabolic inhibition by a variety of medications. The risk of adverse drug-drug interaction(s) is present when metabolic inhibitors are combined with known or suspected substrates of a given enzyme. In the present report the abundantly expressed hepatic enzyme, hCES1, was examined as a potential target of metabolic inhibition by a number of routinely prescribed medications. hCES1 has been seldom assessed in this regard despite its role in the metabolism and detoxification of many compounds. The psychostimulant methylphenidate (MPH) was chosen as an hCES1 selective substrate. In vitro studies were performed using previously developed cell lines which overexpress hCES1 with both p-nitrophenyl acetate and d-MPH serving as known substrates. Aripiprazole, perphenazine, thioridazine, and fluoxetine were determined to be the potent hCES1 inhibitors. A complementary animal study followed in vitro screening studies to further evaluate the inhibitory effect of aripiprazole on CES1 activity in FVB mice. The results suggest that the concurrent administration of racemic (i.e. dl-) MPH with aripiprazole significantly increased the plasma concentrations of both total MPH as well as the less active l-isomer. The ratio of d-MPH and l-MPH plasma concentrations was significantly decreased in the mice treated with aripiprazole compared to the control animals, indicating an overall decrease of CES1 catalytic activity in aripiprazole treated animals. Additionally, a quantitative structure-activity relationship based analysis identified a number of structural similarities of CES1 inhibitors. In conclusion, drug-drug interactions with MPH are likely mediated via CES1 inhibition as a result of concomitant drug therapies. CES1 inhibition represents an overlooked and little studied source of variability in MPH disposition, tolerability, and response.
ESTHER : Zhu_2010_Toxicology_270_59
PubMedSearch : Zhu_2010_Toxicology_270_59
PubMedID: 20097249

Title : Age- and sex-related expression and activity of carboxylesterase 1 and 2 in mouse and human liver - Zhu_2009_Drug.Metab.Dispos_37_1819
Author(s) : Zhu HJ , Appel DI , Jiang Y , Markowitz JS
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 37 :1819 , 2009
Abstract : Carboxylesterase (CES) 1 and CES2 are two major hepatic hydrolases responsible for the metabolism of numerous endogenous and exogenous compounds. In this study, age- and sex-dependent expression and activity of CES1 and CES2 were investigated using both animal models and individual human liver s9 samples. The expression and activity of mouse CES1 (mCES1) and mCES2 in the liver were markedly lower in newborns relative to adults and increased gradually with age, approximating levels of adult animals by age 2 to 4 weeks. Likewise, the average human CES1 (hCES1) expression in the subjects <1 year of age was significantly lower than that of pooled samples. In particular, hCES1 expression in the 13-day and 1-month-old subjects was just 20.3 and 11.1%, respectively, of the pooled sample values. In addition, the subjects <1 year of age exhibited a trend suggestive of low hCES2 expression, but this difference failed to reach statistical significance because of large interindividual variability. The expression and activity of mCES1 and mCES2 were not significantly altered after the animals were treated with human growth hormone, indicating growth hormone may not be associated with the low level of CES expression during early developmental stages. No significant differences of the expression and activity of mCES1 and mCES2 were observed between sexually mature male and female mice. In conclusion, the expression and activity of CES1 and CES2 are age-related but independent of growth hormone level. Sex seems to be an unlikely factor contributing to the regulation of CES1 and CES2.
ESTHER : Zhu_2009_Drug.Metab.Dispos_37_1819
PubMedSearch : Zhu_2009_Drug.Metab.Dispos_37_1819
PubMedID: 19487248

Title : Role of carboxylesterase 1 and impact of natural genetic variants on the hydrolysis of trandolapril - Zhu_2009_Biochem.Pharmacol_77_1266
Author(s) : Zhu HJ , Appel DI , Johnson JA , Chavin KD , Markowitz JS
Ref : Biochemical Pharmacology , 77 :1266 , 2009
Abstract : Carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) are the major hydrolytic enzymes responsible for the metabolism of numerous therapeutic agents as well as endogenous substrates. CES1 and CES2 differ distinctly in their substrate specificity and tissue distribution. In this study, we investigated the role of CES1 and CES2 in converting the antihypertensive prodrug trandolapril to its more active form trandolaprilat, and determined the influence of two newly identified CES1 mutations p.Gly143Glu and p.Asp260fs on trandolapril metabolism. Western blot analysis demonstrated that CES1 is expressed in human liver microsomes (HLM) but not in human intestinal microsomes (HIM). In vitro incubation studies were conducted to contrast the enzymatic activity of HLM as well as HIM upon trandolapril hydrolysis. Trandolapril was rapidly hydrolyzed to its principal active metabolite trandolaprilat after incubation with HLM. In contrast, in HIM, where CES2 is predominantly expressed, incubations did not produce any detectable trandolapril hydrolysis. Furthermore, hydrolysis of trandolapril catalyzed by wild type (WT) and mutant CES1 were assessed utilizing transfected Flp-In-293 cells stably expressing WT CES1 and two variants. WT CES1 efficiently hydrolyzed trandolapril to trandolaprilat with V(max) and K(m) values of 103.6+/-2.2 nmole/min/mg protein and 639.9+/-32.9muM, respectively. However, no appreciable trandolapril hydrolysis could be found after incubation with both p.Gly143Glu and p.Asp260fs variants. Thus, trandolapril appears to be a CES1 selective substrate while CES2 exerts little to no catalytic activity towards this compound. CES1 mutations p.Gly143Glu and p.Asp260fs are essentially dysfunctional enzymes with regard to the conversion of trandolapril to its more active metabolite trandolaprilat.
ESTHER : Zhu_2009_Biochem.Pharmacol_77_1266
PubMedSearch : Zhu_2009_Biochem.Pharmacol_77_1266
PubMedID: 19185566
Gene_locus related to this paper: human-CES1