Ikonnikova Anna, Rodina Tatiana, Dmitriev Artem, Melnikov Evgeniy, Kazakov Ruslan, Nasedkina Tatiana
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.
Federal State Budgetary Institution "Scientific Centre for Expert Evaluation of Medicinal Products" of the Ministry of Health of the Russian Federation, 127051 Moscow, Russia.
J Pers Med. 2022 Apr 5;12(4):580. doi: 10.3390/jpm12040580.
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.
血管紧张素转换酶抑制剂依那普利在肝脏中通过羧酸酯酶1（CES1）水解为活性代谢产物依那普利拉。先前的研究表明，CES1基因中的rs71647871变异会影响依那普利在肝脏样本以及健康志愿者体内的药代动力学。本研究纳入了286例接受依那普利治疗的白种人高血压患者。在后续服药前及服药后4小时，采用高效液相色谱（HPLC）和质谱检测法测定依那普利和依那普利拉的浓度。该研究包括以下基因标记：rs2244613、rs71647871（c.428G>A，p.G143E）以及三个表明CES1A1c亚型存在的单核苷酸多态性（rs12149368、rs111604615和rs201577108）。经临床变量校正后，CES1 rs2244613杂合子的依那普利拉平均峰浓度和谷浓度显著低于AA基因型（分别降低16.6%和19.6%），CC纯合子的依那普利拉平均峰浓度和谷浓度显著低于AA基因型（分别降低32.7%和41.4%）。在CES1A1c纯合子中，经校正的依那普利拉平均浓度比杂合子和野生型（WT）纯合子低75%。CES1基因的药物遗传学标记可能是依那普利个体化给药的一个有前景的预测指标。
