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

Abstract

This 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 (control group, 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 ng/ml x h in the control group versus 310, 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 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.

Impact of carboxylesterase 1 genetic polymorphism on trandolapril activation in human liver and the pharmacokinetics and pharmacodynamics in healthy volunteers

“… 11 , 12 , 15 , 18 , 19 , 21 , 22 However, the clinical impact of the G143E variant differed significantly among drugs metabolized by CES1. For instance, this single‐nucleotide polymorphism (SNP) significantly altered the PKs and PDs of the CES1 substrate medications methylphenidate, 20 , 24 oseltamivir, 22 , 25 and clopidogrel 21 , 26 ; however, it had much less potent effect on the activation of the ACE inhibitor prodrugs enalapril, 28 quinapril, 27 and trandolapril, as we reported in this investigation. Of note, these studies utilized healthy volunteers with similar study designs and sample sizes.…”

“…The clinical relevance of CES1 genetic polymorphisms has been well‐documented for various CES1 substrate medications 23–26,28,34 . A previous in vitro study has demonstrated that trandolapril is selectively activated by CES1 in the human liver, and the CES1 variants, G143E and D260fs, completely impaired trandolapril activation in s9 fractions prepared from cells transfected with the variants 12 .…”

“…Interestingly, the mean AUC 0-∞ of methylphenidate was found to be 152.4% higher in G143E carriers than in controls (p < 0.0001), whereas there was no significant difference between the two groups for enalapril PK parameters. 28 Likewise, Tarkiainen et al performed CES1 G143E pharmacogenetic studies of clopidogrel and two ACE inhibitor prodrugs (enalapril and quinapril) in the same Finnish subjects (carriers = 10 and noncarriers = 12) and revealed similar substrate dependency of the G143E variant's effects on the metabolism of these drugs. Specifically, they reported a 153% decrease of the clopidogrel carboxylic acid to clopidogrel AUC 0-∞ ratios in carriers (p = 0.009), 26 but only a modest 20% decrease for the enalaprilat AUC 0-∞ (p = 0.049) and no significant impact on quinapril PKs.…”

“…Several clinical studies also reported a significant impact of CES1 G143E on the pharmacokinetics (PKs) of the CES1 substrate medications methylphenidate, clopidogrel, and oseltamivir 23–27 . However, the G143E variant showed a negligible effect on the PKs of enalapril and quinapril, although enalapril hydrolysis was markedly impaired by the variant in vitro 11,27,28 . Given the apparent substrate‐dependent effect of CES1 G143E and the discrepancy between the in vitro and in vivo findings, it is difficult to draw conclusions concerning the clinical impact of this CES1 variant on its substrate drugs based solely on in vitro discoveries.…”

Identification of Structural Features for the Inhibition of OAT3-Mediated Uptake of Enalaprilat by Selected Drugs and Flavonoids

“…Enalapril is a prodrug which is hydrolyzed by carboxylesterase 1 (CES1) to form the active metabolite, enalaprilat (Ulm et al, 1982). It has been shown that polymorphism of CES1 affects the pharmacokinetics and pharmacodynamics of enalapril in human subjects (Tarkiainen et al, 2015;Stage et al, 2017). Enalapril is rapidly absorbed with about 40% of the dose (10 mg) converted to enalaprilat (Ulm et al, 1982).…”