Dabigatran etexilate activation is affected by the CES1 genetic polymorphism G143E (rs71647871) and gender

Abstract

The oral anticoagulant prodrug dabigatran etexilate (DABE) is sequentially metabolized by intestinal carboxylesterase 2 (CES2) and hepatic carboxylesterase 1 (CES1) to form its active metabolite dabigatran (DAB). A recent genome-wide association study reported that the CES1 single nucleotide polymorphisms (SNPs) rs2244613 and rs8192935 were associated with lower DAB plasma concentrations in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) study participants. In addition, gender differences in exposure to DAB were observed in clinical studies. The aim of this study was to examine the effect of CES1 genetic polymorphisms and gender on DABE activation using several in vitro approaches. The genotypes of the CES1 SNPs rs2244613, rs8192935, and the known loss-of-function CES1 variant rs71647871 (G143E), and the activation of DABE and its intermediate metabolites M1 and M2 were determined in 104 normal human liver samples. DABE, M1, and M2 activations were found to be impaired in human livers carrying the G143E variant. However, neither rs2244613 nor rs8192935 was associated with the activation in human livers. The incubation study of DABE with supernatant fractions (S9) prepared from the G143E-transfected cells showed that the G143E is a loss-of-function variant for DABE metabolism. Moreover, hepatic CES1 activity on M2 activation was significantly higher in female liver samples than male. Our data suggest that CES1 genetic variants and gender are important contributing factors to variability in DABE activation in humans. A personalized DABE treatment approach based on patient-specific CES1 genotypes and sex may have the potential to improve the efficacy and safety of DABE pharmacotherapy.

A Comprehensive Functional Assessment of Carboxylesterase 1 Nonsynonymous Polymorphisms

“…The discovery of the loss-of-function variant G143E has exemplified the functional significance and clinical implications of CES1 nsSNPs (Zhu et al, 2008). However, only a very few CES1 nsSNPs have been studied so far (Zhu et al, 2008;Shi et al, 2016c;Stage et al, 2017), leaving a large portion of CES1 variability unexplained. Several in silico programs such as SIFT and Polyphen2 were developed to predict functional consequences of nsSNPs.…”

“…CES1 is responsible for the metabolism of a wide range of therapeutic agents, endogenous compounds, and environmental toxins (Laizure et al, 2013). Of particular clinical relevance, CES1 catalyzes the hydrolysis of numerous clinically important medications, such as angiotensin-converting enzyme inhibitor prodrugs (Wang et al, 2016b), clopidogrel (Plavix; Bristol-Myers Squibb, New York, NY) (Zhu et al, 2013), sacubitril (Entresto; Novartis, Basel, Switzerland) (Shi et al, 2016b), methylphenidate (Ritalin; Novartis) (Zhu et al, 2008), oseltamivir (Tamiflu; Genentech, San Francisco, CA) (Shi et al, 2016a), and dabigatran etexilate (Pradaxa; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT) (Laizure et al, 2014;Shi et al, 2016c). Marked interindividual variability in CES1 expression and activity has been well documented (Hosokawa et al, 1995;Shi et al, 2006;Yoshimura et al, 2008;Hagihara et al, 2009;Yang et al, 2009;Zhu et al, 2009a;Ross et al, 2012), which may affect the pharmacokinetics and pharmacodynamics of drugs metabolized by CES1.…”

“…Genetic polymorphisms are increasingly recognized as an important factor contributing to CES1 variability and varied responses to CES1 substrate drugs (Geshi et al, 2005;Zhu et al, 2008;Nemoda et al, 2009;Sai et al, 2010;Rasmussen et al, 2015;Tarkiainen et al, 2015a). For example, the CES1 nonsynonymous single nucleotide polymorphism (nsSNP) G143E (rs71647871) was associated with diminishing CES1 activity on metabolizing several CES1 substrate drugs, including methylphenidate (Zhu et al, 2008;Nemoda et al, 2009;Stage et al, 2017), oseltamivir (Zhu and Markowitz, 2009;Tarkiainen et al, 2012), enalapril (Tarkiainen et al, 2015b;Wang et al, 2016b), clopidogrel (Lewis et al, 2013;Tarkiainen et al, 2015a), dabigatran etexilate (Shi et al, 2016c), and sacubitril (Shi et al, 2016b). These findings indicate that CES1 genetic variants may significantly impact responses to drugs metabolized by CES1.…”

Pharmacogenetics of Novel Oral Anticoagulants: A Review of Identified Gene Variants & Future Perspectives

“…In a recent in vitro study, 104 normal human liver samples of individuals of different racial backgrounds have been investigated for three CES1 SNPs, namely rs2244613, rs8192935 and rs71647871 (or G428A, also referred to as G143E, which is the-loss-of-function CES1 variant) [31,32]. The results imply that G143E mutations are related to the decrease in the activation level of DABE, but the difference between wt and mutant allele carriers did not reach statistical significance.…”

Impact of Abcb1 and Ces1 Genetic Polymorphisms on Trough Steady-State Dabigatran Concentrations in Patients After Endoprosthesis of Knife Join

“…CES1 может иметь мутации в разных аллелях, что обусловливает медленное выведение и высокую концентрацию некоторых лекарственных препаратов в крови [17][18][19].…”