AbstractThis 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 ofCES1: group 1 (control group, n = 16) with twoCES1copies without non‐synonymous SNPs in the exons; group 2 (n = 5) with four copies ofCES1; group 3 (n = 6) harbouring the G143E polymorphism; group 4 (n = 2) with threeCES1copies and increased transcriptional activity of the duplication (CES1A2); group 5 (n = 4) harbouring theCES1A1cvariant; and group 6 (n = 10) with threeCES1copies 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 ng/ml x h in the control groupversus310, 282, 294, 344 and 306 ng/ml x h in groups 2–6, respectively). The terminal half‐life of enalaprilat was significantly longer in group 6 compared with the control group (26.7 hrversus12.7 hr, respectively). However, this was not considered clinically relevant. In conclusion, none of the selected variations ofCES1had a clinically relevant impact on the metabolism of enalapril.