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 the 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. 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. The study team proposes to conduct a multiple-dose healthy volunteer study to evaluate the impact of CES1 genetic variation on the activation, pharmacokinetics, and pharmacodynamics of enalapril, a model ACEI prodrug activated by CES1. The completion of this study will represent a major step towards the establishment of an evidence base from which a more individualized use of ACEI prodrugs can emerge.

Inclusion Criteria:

• Subjects must be male and female (50:50) between the ages of 18-55 years
• Females must have a negative urine pregnancy test prior to the study
• All subjects must have no clinically significant diseases or clinically significant abnormal laboratory values as assessed during the screening medical history, nursing assessment, and laboratory evaluations
• Informed consent must be signed by the eligible subject prior to the initiation of any study procedures

Exclusion Criteria:

• The presence of a known medical condition that would preclude the use of enalapril
• The presence of any surgical or medical condition (active or chronic) that may interfere with drug absorption, distribution, metabolism, or excretion.
• A positive urine pregnancy test in the MCRU prior to the study
• No subjects weighing under 50 kg will be selected
• The lack of use of acceptable methods of birth control unless abstinent
• Subjects who regularly take medications, vitamins, herbal supplements
• The use of any illicit drugs or habitual consumption of large quantities of ethanol (>3 drinks/day)
• The consumption of grapefruit or grapefruit juice a week prior to, and during the study
• Asians will not be included in the study as the CES1 SNP G143E is absent in this population
• Subjects hypersensitive to enalapril
• Subject with a history of angioedema
• Smokers