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

: Tarkiainen EK, Tornio A, Holmberg MT, Launiainen T, Neuvonen PJ, Backman JT, Niemi M

Publisher: WILEY

: 2015

: British Journal of Clinical Pharmacology

: BRITISH JOURNAL OF CLINICAL PHARMACOLOGY

: BRIT J CLIN PHARMACO

: 80

: 5

: 1131

: 1138

: 8

: 0306-5251

DOI: https://doi.org/10.1111/bcp.12667

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 10mg dose of quinapril and enalapril with a washout period of at least 1week. Plasma concentrations of quinapril and quinaprilat were measured for up to 24h and those of enalapril and enalaprilat for up to 48h. Their excretion into the urine was measured from 0h to 12h.ResultsThe area under the plasma concentration-time curve from 0h 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.