Angiotensin-converting enzyme inhibitors (ACEIs) are among the most frequently prescribed medications worldwide for the treatment of essential hypertension, left ventricular systolic dysfunction, acute myocardial infarction, and prevention of the progression of diabetic nephropathy. However, the outcome of ACEI treatment varies significantly between individuals and selected populations. Suboptimal response, therapeutic failure, and significant side effects are commonly documented in patients receiving ACEI therapy. Approximately 80% of the ACEIs available for use in the US are synthesized as esterified prodrugs in order to improve otherwise poor oral bioavailability of the active molecule. The activation of ACEI prodrugs primarily occurs in the liver via metabolic de-esterification of th parent drug. The critical activation step is essential in delivering a successful therapeutic outcome since the active metabolites are approximately 10-1000 times more potent relative to their respective parent compounds. Our group and others have demonstrated that carboxylesterase 1 (CES1), the most abundant hydrolase in the liver, is responsible for the activation of ACEI prodrugs in humans. Marked interindividual variability in CES1 expression and activity has been documented, which results in varied therapeutic efficacy and tolerability of many drugs serving as substrates of CES1. Genetic variation of CES1 is considered to be a major factor contributing to variability in CES1 function. We are among the first demonstrating that some CES1 single nucleotide polymorphisms (SNPs), such as the G143E, are loss-of- function variants, which can significantly affect both pharmacokinetics (PK) and pharmacodynamics (PD) of medications metabolized by CES1. In this proposal, we will test the hypothesis that CES1 genetic variation contributes to interindividual variability of CES1 function, and is one of the determinants influencing the activation and subsequent pharmacological activity of ACEI prodrugs.
Specific Aim 1 is to conduct a multiple- dose healthy volunteer study to evaluate the impact of CES1 genetic variation on the activation, PK, and PD of enalapril, a model ACEI prodrug activated by CES1.
Specific Aim 2 is to identify and characterize functional coding and regulatory CES1 variants that affect the activity and expression of CES1 using several complementary in vitro approaches. The achievement of these stated aims will represent a major step towards the establishment of an evidence base from which a more individualized use of ACEI prodrugs can emerge. This project also has significant potential for the improvement of therapeutic efficacy and safety of many other medications metabolized (activated or deactivated) by CES1.

Public Health Relevance

In this proposal we will determine the functionality of CES1 genetic variants and their impact on the activation and pharmacological activity of ACE inhibitor prodrugs. This project holds great potential to improve the efficacy and safety of pharmacotherapy of ACE inhibitor prodrugs and many other medications metabolized by CES1.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL126969-03
Application #
9417046
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Luo, James
Project Start
2016-02-15
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Piekos, Stephanie C; Chen, Liming; Wang, Pengcheng et al. (2018) Consequences of Phenytoin Exposure on Hepatic Cytochrome P450 Expression during Postnatal Liver Maturation in Mice. Drug Metab Dispos 46:1241-1250
Shi, Jian; Wang, Xinwen; Lyu, Lingyun et al. (2018) Comparison of protein expression between human livers and the hepatic cell lines HepG2, Hep3B, and Huh7 using SWATH and MRM-HR proteomics: Focusing on drug-metabolizing enzymes. Drug Metab Pharmacokinet 33:133-140
Wang, Xinwen; Shi, Jian; Zhu, Hao-Jie (2018) Functional study of Carboxylesterase 1 protein isoforms. Proteomics :e1800288
Shi, Jian; Wang, Xinwen; Zhu, Huaijun et al. (2018) Determining Allele-Specific Protein Expression (ASPE) Using a Novel Quantitative Concatamer Based Proteomics Method. J Proteome Res 17:3606-3612
Wang, Xinwen; Rida, Nada; Shi, Jian et al. (2017) A Comprehensive Functional Assessment of Carboxylesterase 1 Nonsynonymous Polymorphisms. Drug Metab Dispos 45:1149-1155
Shi, Jian; Wang, Xinwen; Nguyen, Jenny-Hoa et al. (2016) Dabigatran etexilate activation is affected by the CES1 genetic polymorphism G143E (rs71647871) and gender. Biochem Pharmacol 119:76-84
Wang, X; Wang, G; Shi, J et al. (2016) CES1 genetic variation affects the activation of angiotensin-converting enzyme inhibitors. Pharmacogenomics J 16:220-30
Shi, Jian; Wang, Xinwen; Eyler, Rachel F et al. (2016) Association of Oseltamivir Activation with Gender and Carboxylesterase 1 Genetic Polymorphisms. Basic Clin Pharmacol Toxicol 119:555-561