The Pharmacokinetics of Enalapril in Relation to CES1 Genotype in Healthy Danish Volunteers
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The Pharmacokinetics of Enalapril in Relation to CES1 Genotype in Healthy Danish Volunteers. / Stage, Claus; Jürgens, Gesche; Guski, Louise Schow; Thomsen, Ragnar; Bjerre, Ditte; Ferrero-Miliani, Laura; Lyauk, Yassine Kamal; Berg Rasmussen, Henrik; Dalhoff, Kim; INDICES Consortium.
In: Basic & Clinical Pharmacology & Toxicology, Vol. 121, No. 6, 06.12.2017, p. 487–492.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The Pharmacokinetics of Enalapril in Relation to CES1 Genotype in Healthy Danish Volunteers
AU - Stage, Claus
AU - Jürgens, Gesche
AU - Guski, Louise Schow
AU - Thomsen, Ragnar
AU - Bjerre, Ditte
AU - Ferrero-Miliani, Laura
AU - Lyauk, Yassine Kamal
AU - Berg Rasmussen, Henrik
AU - Dalhoff, Kim
AU - INDICES Consortium
N1 - This article is protected by copyright. All rights reserved.
PY - 2017/12/6
Y1 - 2017/12/6
N2 - The present study investigated the influence of variations in the carboxylesterase 1 gene (CES1) on the pharmacokinetics of enalapril. Forty-three healthy, Danish, Caucasian volunteers representing different pre-defined genotypes each received 10 mg of enalapril. At specified time points, plasma concentrations of enalapril and the active metabolite enalaprilat were measured. The volunteers were divided into six different groups according to their genetic profile of CES1: Group 1 (controls, n=16) with two CES1 copies without non-synonymous SNPs in the exons; group 2 (n=5) with four copies of CES1; group 3 (n=6) harbouring the G143E polymorphism; group 4 (n=2) with three CES1 copies and increased transcriptional activity of the duplication (CES1A2); group 5 (n=4) harbouring the CES1A1c variant; and group 6 (n=10) with three CES1 copies and the common promoter with low transcriptional activity of the duplication. The median AUC of enalaprilat in the control group was not significantly different from any of the other five groups (297 μg/l x h in the control group versus 310, 282, 294, 344 and 306 μg/l x h in group 2-6, respectively). The terminal half-life of enalaprilat was significantly longer in group 6 compared to the control group (26.7 hr versus 12.7 hr, respectively). However, this was not considered clinically relevant. In conclusion, none of the selected variations of CES1 had a clinically relevant impact on the metabolism of enalapril. This article is protected by copyright. All rights reserved.
AB - The present study investigated the influence of variations in the carboxylesterase 1 gene (CES1) on the pharmacokinetics of enalapril. Forty-three healthy, Danish, Caucasian volunteers representing different pre-defined genotypes each received 10 mg of enalapril. At specified time points, plasma concentrations of enalapril and the active metabolite enalaprilat were measured. The volunteers were divided into six different groups according to their genetic profile of CES1: Group 1 (controls, n=16) with two CES1 copies without non-synonymous SNPs in the exons; group 2 (n=5) with four copies of CES1; group 3 (n=6) harbouring the G143E polymorphism; group 4 (n=2) with three CES1 copies and increased transcriptional activity of the duplication (CES1A2); group 5 (n=4) harbouring the CES1A1c variant; and group 6 (n=10) with three CES1 copies and the common promoter with low transcriptional activity of the duplication. The median AUC of enalaprilat in the control group was not significantly different from any of the other five groups (297 μg/l x h in the control group versus 310, 282, 294, 344 and 306 μg/l x h in group 2-6, respectively). The terminal half-life of enalaprilat was significantly longer in group 6 compared to the control group (26.7 hr versus 12.7 hr, respectively). However, this was not considered clinically relevant. In conclusion, none of the selected variations of CES1 had a clinically relevant impact on the metabolism of enalapril. This article is protected by copyright. All rights reserved.
KW - Journal Article
U2 - 10.1111/bcpt.12835
DO - 10.1111/bcpt.12835
M3 - Journal article
C2 - 28639420
VL - 121
SP - 487
EP - 492
JO - Basic and Clinical Pharmacology and Toxicology
JF - Basic and Clinical Pharmacology and Toxicology
SN - 1742-7835
IS - 6
ER -
ID: 180401806