Effect of carboxylesterase 1 c.428G > A single nucleotide variation on the pharmacokinetics of quinapril and enalapril

Abstract

AIMThe 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. METHODSIn 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. RESULTSThe area under the plasma concentration-time curve from 0 h to infinity (AUC 0-∞ ) 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 AUC 0-∞ 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. CONCLUSIONSThe 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. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Quinapril and enalapril are prodrugs that are hydrolysed in the liver to active metabolites by carboxylesterase 1 (CES1).• The CES1 c.428G > A SNV markedly decreases CES1 activity.• There appear to be no previous studies of the effect of CES1 c.428G > A SNV on the pharmacokinetics of ACE inhibitors in humans. WHAT THIS STUDY ADDS• The CES1 c.428G > A SNV significantly reduced the hydrolytic activation of enalapril, but had no observable effect on quinapril.• These data suggest that CES1 genetic variants can affect the pharmacokinetics of angiotensin-converting enzyme (ACE) inhibitors in humans, and that ACE inhibitors differ in their susceptibility to the effects of CES1 genetic variants.

The Pharmacokinetics of Enalapril in Relation to CES1 Genotype in Healthy Danish Volunteers

“…This is in contrast to our MPH study, in which a markedly (149%) and highly significant increase in d-MPH AUC was found compared to the control group indicating decreased metabolizing capacity [14]. In a recent human study, Tarkiainen et al [12] investigated the impact of the 143E allele on the metabolism of quinapril and enalapril. Both drugs were administered as single 10 mg doses.…”

“…In a recent human study, Tarkiainen et al . investigated the impact of the 143E allele on the metabolism of quinapril and enalapril. Both drugs were administered as single 10 mg doses.…”

The impact of human CES1 genetic variation on enzyme activity assessed by ritalinic acid/methylphenidate ratios

“…Duplication of the gene is the reason for the observed copy number variation . The CES1 G143E variant is the best‐documented polymorphism having an impact on the metabolism of various CES1‐dependent drugs in vivo . Other SNPs have been associated with impaired CES1 activity but not to the same extent as G143E …”

“…6,7 The CES1 G143E variant is the best-documented polymorphism having an impact on the metabolism of various CES1-dependent drugs in vivo. [8][9][10][11][12] Other SNPs have been associated with impaired CES1 activity but not to the same extent as G143E. 13,14 The activity of drug-metabolising enzymes can be estimated by calculating the ratio between the parent drug and its metabolite.…”

Pharmacokinetics After Single Ascending Dose, Food Effect, and Safety of Sacubitril/Valsartan (LCZ696), an Angiotensin Receptor and Neprilysin Inhibitor, in Healthy Japanese Subjects

“…), antiplatelets (clopidogrel), antiviral agents (oseltamivir), central nervous system agents (e.g., meperidine, cocaine) and anticancer agents (capecitabine) [10]. Polymorphisms in CES1 gene can significantly reduce hydrolysis of enalapril but not quinapril [11]. On the other hand, CES1 genetic polymorphism did not affect the hydrolysis of oseltamivir in healthy Japanese subjects [12].…”