Effect of CES1 genetic variation on enalapril steady‐state pharmacokinetics and pharmacodynamics in healthy subjects
Lucy Her, Xinwen Wang, Jian Shi, Hee Jae Choi, Sun Min Jung, Logan S. Smith, Audrey H. Wu, Barry E. Bleske, Hao‐Jie Zhu
Abstract
Aims 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 72 hour PK/PD study. Plasma concentrations of enalapril and its active metabolite enalaprilat were quantified by an established liquid chromatography–tandem mass spectrometry (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*h/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.