Effect of carboxylesterase 1 c.428G > A single nucleotide variation on the pharmacokinetics of quinapril and enalapril.
OBJECTIVE
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-∞) 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-∞ 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.
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
E Katriina
EK
Tarkiainen
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Aleksi
A
Tornio
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Mikko T
MT
Holmberg
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Terhi
T
Launiainen
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Pertti J
PJ
Neuvonen
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Janne T
JT
Backman
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Mikko
M
Niemi
D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000652:urine; D001794:Blood Pressure / Q000187:drug effects; D002265:Carboxylic Ester Hydrolases / Q000235:genetics*; D018592:Cross-Over Studies; D004656:Enalapril / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine; D015773:Enalaprilat / Q000097:blood / Q000652:urine; D005260:Female; D005838:Genotype; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000077583:Quinapril; D044005:Tetrahydroisoquinolines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine; D055815:Young Adult
D000806:Angiotensin-Converting Enzyme Inhibitors; D044005:Tetrahydroisoquinolines; C054501:quinaprilat; D004656:Enalapril; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; D015773:Enalaprilat; D000077583:Quinapril
CES1; carboxylesterase; enalapril; p.G143E; quinapril; rs71647871