The novel carboxylesterase 1 variant c.662A>G may decrease the bioactivation of oseltamivir in humans.
The novel carboxylesterase 1 variant c.662A>G may decrease the bioactivation of oseltamivir in humans.
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DOI：
10.1371/journal.pone.0176320
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Lim KS
中科院分区：
文献类型：
--
作者：
Oh J;Lee S;Lee H;Cho JY;Yoon SH;Jang IJ;Yu KS;Lim KS
人羧酸酯酶1(CES1)是一种丝氨酸酯酶，能降解多种外源性和内源性化合物，包括用于治疗流感的前药奥司他韦。在电子分析中，一种新的CES1 c.662a>；G单核苷酸多态性(SNP)被预测会降低CES1的酶活性。本研究评价了C.662a>；G单核苷酸多态对奥司他韦在人体内的药代动力学的影响。20名健康受试者、8名杂合子c.662a>；G携带者(c.662AG)和12名非携带者(c.662AA)单次口服75 mg奥司他韦。采用LC-MS/MS法测定了奥司他韦及其活性代谢物羧酸奥司他韦的血药浓度和尿药浓度。用非房室方法计算PK参数。计算PK参数的几何平均比值(GMR，C.662AG和C.662AA)及其90%可信区间(CI)。根据奥司他韦的AUC0-48h评估，在c.662AG受试者中，全身暴露于奥司他韦的AUC0-48h增加了10%，而在c.662AG受试者中，奥司他韦羧酸盐的AUC0-48hAUC0-48h降低了5%。代谢率(AUC0-48h，奥司他韦/AUC0-48h，奥司他韦)的GMR和90%CI为0.87(0.66-1.14)。在具有c.662AG基因的受试者中，尿液中不变的奥司他韦排泄量增加了15%。这一结果表明，在这些杂合等位基因携带者中，CES1酶活性可能降低，尽管这种基因变异对CES1底物药物的临床意义值得进一步研究。ClinicalTtrials.gov NCT01902342
Human carboxylesterase 1 (CES1) is a serine esterase that hydrolyses various exogenous and endogenous compounds including oseltamivir, a prodrug used to treat influenza. A novel CES1 c.662A>G single nucleotide polymorphism (SNP) was predicted to decrease CES1 enzymatic activity in an in silico analysis. This study evaluated the effect of the c.662A>G SNP on the pharmacokinetics (PK) of oseltamivir in humans. A single oral dose of oseltamivir at 75 mg was administered to 20 healthy subjects, 8 heterozygous c.662A>G carriers (c.662AG) and 12 non-carriers (c.662AA). The concentrations of oseltamivir and its active metabolite, oseltamivir carboxylate, were measured in plasma and urine using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The PK parameters were calculated using a noncompartmental method. The geometric mean ratios (GMR, c.662AG to c.662AA) of the PK parameters and their 90% confidence intervals (CI) were calculated. The systemic exposure to oseltamivir, as assessed by the AUC0-48h of oseltamivir, was increased by 10% in c.662AG subjects, whereas the AUC0-48h of oseltamivir carboxylate was 5% lower in c.662AG subjects. The GMR and 90% CI of the metabolic ratio (AUC0-48h, Oseltamivir carboxylate/AUC0-48h, Oseltamivir) was 0.87 (0.66–1.14). The amount of unchanged oseltamivir excreted in the urine was increased by 15% in subjects with the c.662AG genotype. This result suggests that CES1 enzymatic activity may be decreased in these heterozygous allele carriers, although further studies are warranted to investigate the clinical implications of this genetic variation on CES1 substrate drugs. ClinicalTtrials.gov NCT01902342