Key result
CES1 rs2244613 CC genotype linked to ~33% lower peak enalaprilat levels vs AA genotype.
Why the study?
CES1 variant rs71647871 affects enalapril pharmacokinetics in liver samples and healthy volunteers, but the influence of CES1 genotypes in hypertensive patients remained to be evaluated.
Does the CES1 genotype alter the pharmacokinetics (peak and trough enalaprilat concentrations) in patients with arterial hypertension receiving enalapril?
Observational (n=286)
Does the CES1 genotype alter the pharmacokinetics (peak and trough enalaprilat concentrations) in patients with arterial hypertension receiving enalapril?
Effect estimate: 32.7% lower peak and 41.4% lower trough concentration in CC homozygotes vs AA genotype
p-value: p=0.027
CES1 genetic variants, particularly rs2244613, significantly alter enalaprilat pharmacokinetics and might be useful to guide individualized enalapril dosing.
CES1 rs2244613 CC genotype was associated with lower enalaprilat levels; leaves open whether genotyping should guide dosing in hypertension.
The angiotensin-converting enzyme inhibitor enalapril is hydrolysed to an active metabolite, enalaprilat, in the liver via carboxylesterase 1 (CES1). Previous studies show that variant rs71647871 in the CES1 gene affects the pharmacokinetics of enalapril on liver samples as well as healthy volunteers. This study included 286 Caucasian patients with arterial hypertension who received enalapril. The concentrations of enalapril and enalaprilat were determined before subsequent intake of the drug and 4 h after it with high-performance liquid chromatography (HPLC) and mass spectrometric detection. The study included genetic markers as follows: rs2244613, rs71647871 (c.428G>A, p.G143E) and three SNPs indicating the presence of a subtype CES1A1c (rs12149368, rs111604615 and rs201577108). Mean peak and trough enalaprilat concentrations, adjusted by clinical variables, were significantly lower in CES1 rs2244613 heterozygotes (by 16.6% and 19.6%) and in CC homozygotes (by 32.7% and 41.4%) vs. the AA genotype. In CES1A1c homozygotes, adjusted mean enalaprilat concentrations were 75% lower vs. heterozygotes and wild-type (WT) homozygotes. Pharmacogenetic markers of the CES1 gene may be a promising predictor for individualisation when prescribing enalapril.
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Ikonnikova et al. (2022) conducted an observational in Arterial Hypertension (n=286). CES1 genotype variants (rs2244613 and CES1A1c) vs. Wild-type genotype was evaluated on Peak and trough plasma enalaprilat concentrations (32.7% lower peak and 41.4% lower trough concentration in CC homozygotes vs AA genotype, p=0.027). In patients taking enalapril, the CES1 rs2244613 CC genotype was associated with significantly lower peak and trough enalaprilat concentrations by 32.7% and 41.4% respectively, compared to the AA genotype.
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