Effect of CES1 genetic variation on enalapril steady‐state pharmacokinetics and pharmacodynamics in healthy subjects

Abstract

A previous in vitro study demonstrated the CES1 genetic variant, G143E (rs71647871), significantly impaired enalapril activation. Two previous clinical studies examined the impact of G143E on single-dose enalapril PK (10 mg); however, the results were inconclusive. A prospective, multi-dose, pharmacokinetics and pharmacodynamics (PK/PD) study was conducted to determine the impact of the CES1 G143E variant on enalapril steady-state PK and PD in healthy volunteers. Methods: Study participants were stratified to G143E non-carriers (n = 15) and G143E carriers (n = 6). All the carriers were G143E heterozygotes. Study subjects received enalapril 10 mg daily for seven consecutive days prior to a 72 hour PK/PD study. Plasma concentrations of enalapril and its active metabolite enalaprilat were quantified by an established liquid chromatography-tandem mass spectrometry (LC-MS/MS) method.Results: The CES1 G143E carriers had 30.9% lower enalaprilat C max (P = 0.03) compared to the non-carriers (38.01 vs. 55.01 ng/mL). The carrier group had 27.5% lower AUC 0-∞ (P = 0.02) of plasma enalaprilat compared to the non-carriers (374.29 vs. ng*h/mL). The carriers also had a 32.3% lower enalaprilat-to-enalapril AUC 0-∞ ratio (P = 0.003) relative to the non-carriers. The average maximum reduction of systolic blood pressure in the non-carrier group was approximately 12.4% at the end of the study compared to the baseline (P = 0.001). No statistically significant blood pressure reduction was observed in the G143E carriers. Conclusions:The CES1 loss-of-function G143E variant significantly impaired enalapril activation and its systolic blood pressure-lowering effect in healthy volunteers.angiotensin-converting enzyme (ACE) inhibitors, carboxylesterase 1 (CES1), enalapril, pharmacogenetics, pharmacokinetics Principal investigator statement: The authors confirm that the Principal Investigator for this paper is Hao-Jie Zhu and that he had direct clinical responsibility for patients.ClinicalTrials.gov Identifier: NCT03051282

Plasma Carboxylesterase 1 Predicts Methylphenidate Exposure: A Proof‐of‐Concept Study Using Plasma Protein Biomarker for Hepatic Drug Metabolism

“…In particular, many investigations have explored the effects of genetic polymorphisms on the activity and expression of CES1 and ensuing impacts on the PK and clinical outcomes of CES1 substrate drugs. However, while several CES1 genetic variants have been found to affect CES1 activity and expression, only the nonsynonymous variant G143E showed consistent effects on both the PK and PD of CES1 substrates such as methylphenidate, clopidogrel, and enalapril 13,14,27–31 . It should be noted that the G143E variant impairs CES1 catalytic activity without altering CES1 expression, and hepatic CES1 expression varies markedly among individuals having the same G143E genotype 10,11 .…”

“…It should be noted that the G143E variant impairs CES1 catalytic activity without altering CES1 expression, and hepatic CES1 expression varies markedly among individuals having the same G143E genotype 10,11 . Similarly, the PK of CES1 substrate drugs differed significantly among subjects in the same G143E genotype group 28,30–32 . Therefore, beyond the G143E variant, the identification of a reliable biomarker of hepatic CES1 protein expression is of significant clinical interest.…”

“…10,11 Similarly, the PK of CES1 substrate drugs differed significantly among subjects in the same G143E genotype group. 28,[30][31][32] Therefore, beyond the G143E variant, the identification of a reliable biomarker of hepatic CES1 protein expression is of significant clinical interest. Our findings suggest that plasma CES1 protein has the potential to be developed as a The plasma proteome is dominated by several highly abundant proteins (e.g., albumin) and has a large dynamic range in protein concentration, 33,34 making it challenging to quantify low-abundance plasma proteins.…”

“…However, while several CES1 genetic variants have been found to affect CES1 activity and expression, only the nonsynonymous variant G143E showed consistent effects on both the PK and PD of CES1 substrates such as methylphenidate, clopidogrel, and enalapril. 13,14,[27][28][29][30][31] It should be noted that the G143E variant impairs CES1 catalytic activity without altering CES1 expression, and hepatic CES1 expression varies markedly among individuals having the same G143E genotype. 10,11 Similarly, the PK of CES1 substrate drugs differed significantly among subjects in the same G143E genotype group.…”

The Influence of Structural Variants of the CES1 Gene on the Pharmacokinetics of Enalapril, Presumably Due to Linkage Disequilibrium with the Intronic rs2244613

“…It has been shown that the activity of the enzyme can critically depend on the genetic variants of the CES1 gene. Accordingly, markers in the CES1 gene play a role in interindividual differences in the metabolism and effect numerous drugs that are substrates of this enzyme [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. Thus, single nucleotide polymorphisms (SNPs) are known in the CES1 gene that lead to a change in the activity of the enzyme, for example, G143E (rs71647871) [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ] and variant 1168-33C>A in intron 10 (rs2244613) [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 20 ].…”