Effect of CES1 genetic variation on enalapril steady-state pharmacokinetics and pharmacodynamics in healthy subjects.

Effect of CES1 genetic variation on enalapril steady-state pharmacokinetics and pharmacodynamics in healthy subjects.

Her LH; Wang X; Shi J; Choi HJ; Jung SM; Smith LS; Wu AH; Bleske Barry E; Zhu H-J

British Journal Of Clinical Pharmacology

2021

2021-05-07

Background and Objective: Enalapril is a prodrug and needs to be activated by carboxylesterase 1 (CES1). A previous in vitro study demonstrated the CES1 genetic variant, G143E (rs71647871), significantly impaired enalapril activation. Two previous clinical studies examined the impact of G143E on single-dose enalapril PK (10 mg); however, the results were inconclusive. A prospective, multi-dose, pharmacokinetics, and pharmacodynamics (PK/PD) study was conducted to determine the impact of the CES1 G143E variant on enalapril steady-state PK and PD in healthy volunteers.; Methods: Study participants were stratified to G143E non-carriers (n=15) and G143E carriers (n=6). All the carriers were G143E heterozygotes. Study subjects received enalapril 10 mg daily for seven consecutive days prior to a 72h PK/PD study. Plasma concentrations of enalapril and its active metabolite enalaprilat were quantified by an established LC-MS/MS method.; Results: The CES1 G143E carriers had 30.9% lower enalaprilat C max (P = 0.03) compared to the non-carriers (38.01 vs. 55.01 ng/mL). The carrier group had 27.5% lower AUC 0-∞ (P = 0.02) of plasma enalaprilat compared to the non-carriers (374.29 vs. 515.91 ng*hr/mL). The carriers also had a 32.3% lower enalaprilat-to-enalapril AUC 0-∞ ratio (P = 0.003) relative to the non-carriers. The average maximum reduction of systolic blood pressure in the non-carrier group was approximately 12.4% at the end of the study compared to the baseline (P = 0.001). No statistically significant blood pressure reduction was observed in the G143E carriers.; Conclusions: The CES1 loss-of-function G143E variant significantly impaired enalapril activation and its systolic blood pressure-lowering effect in healthy volunteers. (This article is protected by copyright. All rights reserved.)

pharmacokinetics; angiotensin-converting enzyme (ACE) inhibitors; Carboxylesterase1 (CES1); enalapril; pharmacogenetics

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journalArticle

1365-2125

NEOMED College of Pharmacy

Department of Pharmaceutical Sciences

May 2021 List