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.