College of Pharmacy, University of Michigan, Ann Arbor, MI, United States.
Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH, United States.
Br J Clin Pharmacol. 2021 Dec;87(12):4691-4700. doi: 10.1111/bcp.14888. Epub 2021 May 26.
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.
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.
The CES1 G143E carriers had 30.9% lower enalaprilat C (P = 0.03) compared to the non-carriers (38.01 vs. 55.01 ng/mL). The carrier group had 27.5% lower AUC (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 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.
The CES1 loss-of-function G143E variant significantly impaired enalapril activation and its systolic blood pressure-lowering effect in healthy volunteers.
依那普利是一种前体药物，需要被羧基酯酶 1（CES1）激活。先前的一项体外研究表明，CES1 遗传变异 G143E（rs71647871）显著降低了依那普利的激活作用。两项先前的临床研究检测了 G143E 对单剂量依那普利药代动力学（10mg）的影响，但结果尚无定论。本研究进行了一项前瞻性、多剂量药代动力学和药效学（PK/PD）研究，以确定 CES1 G143E 变异对健康志愿者依那普利稳态 PK 和 PD 的影响。
将研究参与者分为 CES1 G143E 非携带者（n=15）和 G143E 携带者（n=6）。所有携带者均为 G143E 杂合子。所有受试者连续 7 天每日接受依那普利 10mg 治疗，随后进行 72 小时 PK/PD 研究。采用建立的液相色谱-串联质谱（LC-MS/MS）法测定依那普利及其活性代谢物依那普利拉的血浆浓度。
与非携带者（38.01 vs. 55.01ng/mL）相比，CES1 G143E 携带者的依那普利拉 C 降低了 30.9%（P=0.03）。与非携带者（374.29 vs. 515.91ng*h/mL）相比，携带者组的血浆依那普利拉 AUC 降低了 27.5%（P=0.02）。携带者的依那普利拉与依那普利 AUC 比值也降低了 32.3%（P=0.003）。非携带者组在研究结束时收缩压平均最大降低约 12.4%，与基线相比（P=0.001）。G143E 携带者组未观察到血压的统计学显著降低。
CES1 失功能 G143E 变异显著降低了健康志愿者依那普利的激活及其降低收缩压的作用。
