Angiotensin-converting enzyme inhibitors (ACEIs) are among the most commonly prescribed medications worldwide, and are frequently used in patients with chronic kidney disease (CKD) for the treatment of hypertension, heart failure, and deceleration of the progression of nephropathy. However, the outcome of ACEI treatment varies significantly between individuals, and therapeutic failure and significant side effects are commonly documented in patients receiving ACEIs. The underlying mechanisms of inter individual variability in response to ACEI therapy currently remain inconclusive. There is a critical need to identify the factors affecting therapeutic outcomes of ACEIs in order to improve efficacy and safety of ACEI pharmacotherapy. Of note, the majority of ACEIs are synthesized as esterified pro-drugs in order to improve otherwise poor oral bioavailability of the active molecule The activation of ACEI pro-drugs primarily occurs in the liver via metabolic de-esterification of the parent drugs. This critical activation step is essential in delivering a successful therapeutic outcome. Our group and others have demonstrated that hepatic carboxylesterase 1 (CES1) is responsible for the activation of ACEI pro-drugs in humans. Marked inter-individual variability in CES1 expression and activity has been documented, which results in varied metabolisms, therapeutic efficacy, and tolerability of drugs serving as the substrates of CES1. Genetic variation of CES1 is increasingly recognized as the major factor contributing to variability in CES1 function. We have discovered the first clinically important CES1 variants G143E, and demonstrated that the G143E is a loss-of-function variant with regard to activating ACEI pro-drugs in vitro. In this proposal, we will test the hypothesis that CES1 genetic variation is one of the foremost determinants influencing the activation and subsequent pharmacokinetics and pharmacodynamics of ACEI pro-drugs.
The Specific Aim i s to conduct a healthy volunteer study to determine the impact of the CES1 G143E on the activation and pharmacological activity of enalapril, a model ACEI pro-drug activated by CES1. At the completion of this project, we would have established a critical role of CES1 variants in the pharmacokinetics and pharmacodynamics of ACEI pro-drugs. The data generated from this exploratory project will form the foundation from which a comprehensive CES1 pharmacogenetic study can be launched to elucidate the function of CES1 variants and determine the impact of those variants on therapeutic outcomes of AECI pro-drugs. Our long-term goal is to optimize ACEI pharmacotherapy via clinical implementation of CES1 pharmacogenetics. This project also has a great potential for the improvement of therapeutic efficacy and safety of many other medications metabolized by CES1.

Public Health Relevance

The present proposal is to determine the impact of CES1 genetic variants on the activation and pharmacological activity of ACE inhibitor prodrugs. This project holds great potential to improve the efficacy and safety of ACE inhibitor prodrugs in patients with CKD and many other indications.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Kidney, Nutrition, Obesity and Diabetes (KNOD)
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Eldadah, Basil A
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University of Michigan Ann Arbor
Schools of Pharmacy
Ann Arbor
United States
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Zhu, Hao-Jie; Langaee, Taimour Y; Gong, Yan et al. (2016) CES1P1 variant -816A>C is not associated with hepatic carboxylesterase 1 expression and activity or antihypertensive effect of trandolapril. Eur J Clin Pharmacol 72:681-7
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