Several single nucleotide variations (SNVs) affect carboxylesterase 1 (CES1) activity, but the effects of genetic variants on CES1 gene expression have not been systematically investigated. Therefore, our aim was to investigate effects of genetic variants on CES1 gene expression in two independent whole blood sample cohorts of 192 (discovery) and 88 (replication) healthy volunteers and in a liver sample cohort of 177 patients. Furthermore, we investigated possible effects of the found variants on clopidogrel pharmacokinetics (n = 106) and pharmacodynamics (n = 46) in healthy volunteers, who had ingested a single 300 mg or 600 mg dose of clopidogrel. Using massively parallel sequencing, we discovered two CES1 SNVs, rs12443580 and rs8192935, to be strongly and independently associated with a 39% (p = 4.0 x 10(-13) ) and 31% (p = 2.5 x 10(-8) ) reduction in CES1 whole blood expression per copy of the minor allele. These findings were replicated in the replication cohort. However, these SNVs did not affect CES1 liver expression, or clopidogrel pharmacokinetics or pharmacodynamics. Conversely, the CES1 c.428G>A missense SNV (rs71647871) impaired the hydrolysis of clopidogrel, increased exposure to clopidogrel active metabolite and enhanced its antiplatelet effects. In conclusion, the rs12443580 and rs8192935 variants reduce CES1 expression in whole blood but not in the liver. These tissue-specific effects may result in substrate-dependent effects of the two SNVs on CES1-mediated drug metabolism.
Carboxylesterase 1 (CES1) hydrolyzes the prodrug clopidogrel to an inactive carboxylic acid metabolite. We studied the pharmacokinetics and pharmacodynamics of 600 mg oral clopidogrel in healthy white volunteers, including 10 carriers and 12 noncarriers of CES1 c.428G>A (p.Gly143Glu, rs71647871) single nucleotide variation (SNV). Clopidogrel carboxylic acid to clopidogrel area under the plasma concentration-time curve from 0 hours to infinity (AUC0-infinity ) ratio was 53% less in CES1 c.428G>A carriers than in noncarriers (P = 0.009), indicating impaired hydrolysis of clopidogrel. Consequently, the AUC0-infinity of clopidogrel and its active metabolite were 123% (P = 0.004) and 67% (P = 0.009) larger in the c.428G>A carriers than in noncarriers. Consistent with these findings, the average inhibition of P2Y12 -mediated platelet aggregation 0-12 hours after clopidogrel intake was 19 percentage points higher in the c.428G>A carriers than in noncarriers (P = 0.036). In conclusion, the CES1 c.428G>A SNV increases clopidogrel active metabolite concentrations and antiplatelet effects by reducing clopidogrel hydrolysis to inactive metabolites.
AIM: The aim of the present study was to investigate the effects of the carboxylesterase 1 (CES1) c.428G > A (p.G143E, rs71647871) single nucleotide variation (SNV) on the pharmacokinetics of quinapril and enalapril in a prospective genotype panel study in healthy volunteers. METHODS: In a fixed-order crossover study, 10 healthy volunteers with the CES1 c.428G/A genotype and 12 with the c.428G/G genotype ingested a single 10 mg dose of quinapril and enalapril with a washout period of at least 1 week. Plasma concentrations of quinapril and quinaprilat were measured for up to 24 h and those of enalapril and enalaprilat for up to 48 h. Their excretion into the urine was measured from 0 h to 12 h. RESULTS: The area under the plasma concentration-time curve from 0 h to infinity (AUC0-infinity ) of active enalaprilat was 20% lower in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (95% confidence interval of geometric mean ratio 0.64, 1.00; P = 0.049). The amount of enalaprilat excreted into the urine was 35% smaller in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (P = 0.044). The CES1 genotype had no significant effect on the enalaprilat to enalapril AUC0-infinity ratio or on any other pharmacokinetic or pharmacodynamic parameters of enalapril or enalaprilat. The CES1 genotype had no significant effect on the pharmacokinetic or pharmacodynamic parameters of quinapril. CONCLUSIONS: The CES1 c.428G > A SNV decreased enalaprilat concentrations, probably by reducing the hydrolysis of enalapril, but had no observable effect on the pharmacokinetics of quinapril.
Bioactivation of the antiviral agent oseltamivir to active oseltamivir carboxylate is catalyzed by carboxylesterase 1 (CES1). After the screening of 860 healthy Finnish volunteers for the CES1 c.428G>A (p.Gly143Glu, rs121912777) polymorphism, a pharmacokinetic study with 75 mg oseltamivir was carried out in c.428G>A carriers and noncarriers. Heterozygous c.428GA carriers (n = 9) had 18% larger values of oseltamivir area under the plasma concentration-time curve from 0 h to infinity (AUC(0-infinity)) (P = 0.025) and 23% smaller carboxylate-to-oseltamivir AUC(0-infinity) ratio (P = 0.006) than noncarriers (n = 12). This shows that the CES1 c.428G>A polymorphism impairs oseltamivir bioactivation in humans.
