Carboxylesterase 1 as a Determinant of Clopidogrel Metabolism and Activation

Abstract

Clopidogrel pharmacotherapy is associated with substantial interindividual variability in clinical response, which can translate into an increased risk of adverse outcomes. Clopidogrel, a recognized substrate of hepatic carboxylesterase 1 (CES1), undergoes extensive hydrolytic metabolism in the liver. Significant interindividual variability in the expression and activity of CES1 exists, which is attributed to both genetic and environmental factors. We determined whether CES1 inhibition and CES1 genetic polymorphisms would significantly influence the biotransformation of clopidogrel and alter the formation of the active metabolite. Coincubation of clopidogrel with the CES1 inhibitor bis(4-nitrophenyl) phosphate in human liver s9 fractions significantly increased the concentrations of clopidogrel, 2-oxo-clopidogrel, and clopidogrel active metabolite, while the concentrations of all formed carboxylate metabolites were significantly decreased. As anticipated, clopidogrel and 2-oxoclopidogrel were efficiently hydrolyzed by the cell s9 fractions prepared from wild-type CES1 transfected cells. The enzymatic activity of the CES1 variants G143E and D260fs were completely impaired in terms of catalyzing the hydrolysis of clopidogrel and 2-oxo-clopidogrel. However, the natural variants G18V, S82L, and A269S failed to produce any significant effect on CES1-mediated hydrolysis of clopidogrel or 2-oxo-clopidogrel. In summary, deficient CES1 catalytic activity resulting from CES1 inhibition or CES1 genetic variation may be associated with higher plasma concentrations of clopidogrel-active metabolite, and hence may enhance antiplatelet activity. Additionally, CES1 genetic variants have the potential to serve as a biomarker to predict clopidogrel response and individualize clopidogrel dosing regimens in clinical practice.

Genetic Polymorphisms of theCarboxylesterase 1(CES1) Gene in a Korean Population

“…[2,8,16] In addition, the allele frequency of the -816A>C polymorphism was 30.9%, 23.8%, and 24.8% in Chinese Yao population, Chinese Han population, and Japanese, respectively. [14,17] As expected, the G143E polymorphism, which has been reported to be 0% in Asian populations [2,8,16] and the D260fs polymorphism, which has been observed to be a rare variant in all ethnic groups [15] were not found in this study. On the other hand, the -816A>C variants, which has been reported more than 20% in Asian, were not observed in this study.…”

“…[14,15] Studies examining the potential therapeutic implications of CES1 gene variants have been extensively investigated and reported in biomedical literature. [2,15] In this study, we evaluated the frequencies of the CES1 genetic variations and their allele and haplotype frequencies in Koreans. The SNP -914G>C showed the highest rate of CES1 gene polymorphism.…”

“…In previously performed invitro functional studies, the CES1 variants G18V and A269S did not produce significant effects on CES1 mediated metabolism of substrates including clopidogrel and methylphenidate. [15] However, the effect of E221G (11657A>G, rs200707504; 2% frequency in Koreans) on CES1 enzymatic activity has not been characterized to date. Therefore, additional studies, including in-vitro functional analysis and clinical studies in humans, are needed to elucidate the role of the E221G variant in phase I drug biotransformation.…”

Substrate-competitive activity-based profiling of ester prodrug activating enzymes

“…Human liver carboxylesterase 1 (CES1) is a known activating enzyme of several ester prodrugs, including oseltamivir 5,[15][16][17][18] . The co-expression of multiple carboxylesterase (CES) genes 19,20 and the differential substrate preferences between species complicates direct analysis of contributions from distinct CES enzymes.…”

A population‐based study of the drug interaction between clopidogrel and angiotensin converting enzyme inhibitors

“…However, important pharmacologic differences exist among the drugs in this class. Most commonly prescribed ACE inhibitors (including ramipril, trandolapril, enalapril and perindopril) are prodrugs that are de‐esterified to active metabolites (ramiprilat, trandolaprilat, emalaprilat and perindoprilat, respectively) by the enzyme carboxylesterase 1 (CES1), an enzyme highly expressed in liver and increasingly appreciated as an important factor in drug metabolism 9, 10, 11, 12. In contrast, lisinopril and captopril are active ACE inhibitors that require no such bio‐activation 13.…”