The functional G143E variant of carboxylesterase 1 is associated with increased clopidogrel active metabolite levels and greater clopidogrel response

Abstract

Introduction Carboxylesterase 1 (CES1) is the primary enzyme responsible for converting clopidogrel into biologically inactive carboxylic acid metabolites. Methods We genotyped a functional variant in CES1, G143E, in participants of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) study (n=566) and in 350 patients with coronary heart disease treated with clopidogrel, and carried out an association analysis of bioactive metabolite levels, on-clopidogrel ADP-stimulated platelet aggregation, and cardiovascular outcomes. Results The levels of clopidogrel active metabolite were significantly greater in CES1 143E-allele carriers (P = 0.001). Consistent with these findings, individuals who carried the CES1 143E-allele showed a better clopidogrel response as measured by ADP-stimulated platelet aggregation in both participants of the PAPI study (P = 0.003) and clopidogrel-treated coronary heart disease patients (P = 0.03). No association was found between this single nucleotide polymorphism and baseline measures of platelet aggregation in either cohort. Conclusion Taken together, these findings suggest, for the first time, that genetic variation in CES1 may be an important determinant of the efficacy of clopidogrel.

In Vitro Drug Metabolism by Human Carboxylesterase 1: Focus on Angiotensin-Converting Enzyme Inhibitors

“…Additionally, genetic variations that cause reduced expression and/or activity of CES1 may further increase this possibility. Polymorphisms in the gene or promoter region for CES1 have been shown to cause significant changes in the pharmacokinetics of and/or the clinical response to methylphenidate, oseltamivir, clopidogrel, and imidapril (Geshi et al, 2005;Zhu et al, 2008;Tarkiainen et al, 2012;Lewis et al, 2013). Individuals with CES1 polymorphisms that produce a poor CES1 phenotype in relation to metabolism of substrates, may be at increased risk of experiencing drug interactions that involve CES1 substrates and inhibitors.…”

In Vitro Hydrolysis and Transesterification of CDP323, an α4β1/α4β7 Integrin Antagonist Ester Prodrug

“…This enzymatic instability makes bioanalysis in rodent plasma quite difficult. In addition, there is more and more evidence of CES polymorphism impairing the pharmacokinetics of the ester prodrug, thus requiring special attention in clinical trials (Lewis et al, 2013;Suzaki et al, 2013).…”

Genetics of Clopidogrel Resistance: Recent Data

“…В отличие от PON-1, многообещающие перспек-тивы имеются в отношении двух других генов -CES1 [33] и CYP4F2 [34].…”

“…Zhu HJ, et al [36] было установлено, что носительство поли-морфизма G143E (rs71647871) гена CES1 ассоцииро-вано с потерей гидролитической активности карбок-силэстеразы-1, что может стать причиной повыше-ния плазменной концентрации активного метаболита клопидогреля и повышения антиагрегантного эффекта. Действительно, в исследовании PAPI [33] было продемонстрировано, что гетерозиготные носи-тели аллельного варианта 143Е имеют статистически значимо более высокую концентрацию активного метаболита клопидогреля (30,3±6,1 против 19,0±0,4 нг/мл, соответственно; р=0,001) и более выраженное ингибирование тромбоцитов (оптиче-ская агрегометрия -25% и 45%, соответственно; p=0,03) по сравнению с гомозиготными носителями аллеля 143G. Однако разница в частоте развития сердечно-сосудис тых событий через год оказалась статистически незначимой (13,7% и 0,0%, соответ-ственно; р=0,44).…”