Carboxylesterase 1 Polymorphism Impairs Oseltamivir Bioactivation in Humans

Tarkiainen, E. Katriina; Backman, Janne T.; Neuvonen, Mikko; Neuvonen, Pertti J.; Schwab, Matthias; Niemi, Mikko

doi:10.1038/clpt.2012.13

Cited by 67 publications

(70 citation statements)

References 17 publications

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“…[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.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…[2,5,8,14,16] The minor allele frequency (MAF) of G143E was estimated to be 3.7%, 4.3%, 2.0%, and 0% in European-American, African-American, Hispanic, and Asian populations, respectively. [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.…”

Section: Discussionmentioning

confidence: 99%

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

Jung

Jeong

Shin

et al. 2014

Transl Clin Pharmacol

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Human carboxylesterase 1 (CES1) is a serine esterase that hydrolyzes various exogenous compounds. Single nucleotide polymorphisms (SNPs) of CES1 may lead to inter-individual metabolic variability of its substrates. The allele and haplotype frequencies of known SNPs have been demonstrated to vary among ethnic groups. We analyzed genetic variations of CES1 in a Korean population. Direct sequencing of all exons and flanking regions of the CES1 gene was performed on samples obtained from 200 Koreans. We identified 41 SNPs. The most frequent SNPs was -914G>C (frequency: 99.5%), followed by 4256G>A (frequency: 65.8%), -75T>G (frequency: 59.3%). Haplotype analysis using the identified SNPs revealed fifteen haplotypes (≥1% haplotype frequency) in our samples. The most frequent haplotype was Hap1 (frequency: 15.4%). Among the identified 41 SNPs, nine of which are novel variants and 14 SNPs were nonsynonymous variants. Using the functional predictive software PolyPhen-2, the G19V, E221G, and A270S variants were predicted to be most likely damaging to the function and structure of CES1. In-vitro analyses for two of these variants have been previously performed; however, functional evaluation of E221G (11657A>G, rs200707504) still needs to be conducted. Therefore, further studies are warranted to characterize the functional impact of E221G on CES1 activity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Jung

Jeong

Shin

et al. 2014

Transl Clin Pharmacol

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

2013

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Carboxylesterase 1 (CES1) is the major hydrolase in human liver. The enzyme is involved in the metabolism of several important therapeutic agents, drugs of abuse, and endogenous compounds. However, no studies have described the role of human CES1 in the activation of two commonly prescribed angiotensinconverting enzyme inhibitors: enalapril and ramipril. Here, we studied recombinant human CES1-and CES2-mediated hydrolytic activation of the prodrug esters enalapril and ramipril, compared with the activation of the known substrate trandolapril. Enalapril, ramipril, and trandolapril were readily hydrolyzed by CES1, but not by CES2. Ramipril and trandolapril exhibited Michaelis-Menten kinetics, while enalapril demonstrated substrate inhibition kinetics. Intrinsic clearances were 1.061, 0.360, and 0.02 ml/min/mg protein for ramipril, trandolapril, and enalapril, respectively. Additionally, we screened a panel of therapeutic drugs and drugs of abuse to assess their inhibition of the hydrolysis of p-nitrophenyl acetate by recombinant CES1 and human liver microsomes. The screening assay confirmed several known inhibitors of CES1 and identified two previously unreported inhibitors: the dihydropyridine calcium antagonist, isradipine, and the immunosuppressive agent, tacrolimus. CES1 plays a role in the metabolism of several drugs used in the treatment of common conditions, including hypertension, congestive heart failure, and diabetes mellitus; thus, there is a potential for clinically relevant drug-drug interactions. The findings in the present study may contribute to the prediction of such interactions in humans, thus opening up possibilities for safer drug treatments.

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“…In addition, genetic polymorphism has been reported for CES genes which impacts on the bioactivation of ester prodrugs in human (Tarkiainen et al, 2012), especially in terms of interindividual variability in drug disposition (Zhu and Markowitz, 2013).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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We identified the enzyme(s) involved in the hydrolysis of the ethyl ester prodrug CDP323 (C 28 H 29 BrN 4 0 3 ) and characterized its transesterification in the presence of ethanol with special emphasis on the risks of drug-drug interaction. The hydrolysis of CDP323 was evaluated in vitro using human liver and intestinal microsomes and recombinant human carboxylesterases (hCES1 and 2) and was shown to be approximately 20-fold higher in human liver microsomes when compared with human intestinal microsomes and in hCES1 when compared with hCES2. Nonspecific inhibitors of carboxylesterases significantly inhibited the hydrolysis of CDP323 (>80% inhibition) while specific inhibitors of CES2, acetylcholine esterase, arylesterase, and butyrylcholinesterase did not impair the hydrolysis reaction. The effect of ethanol on the kinetic parameters for hydrolysis was investigated, demonstrating that at high concentration (2%), Michaelis-Menten constant (K m ), maximum velocity (V max ), and intrinsic clearance (CL int ) for the formation of the hydrolyzed product were decreased (∼40%). The use of deuterated ethanol allowed more mechanistic investigations of the transesterification mechanism and showed that the intrinsic clearance based on parent loss was not impaired in the presence of alcohol. Overall, our data demonstrate that CDP323 is mainly hydrolyzed by hCES1 and is prone to transesterification in the presence of ethanol. Transesterification mechanisms compete with hydrolysis without impairing the overall clearance of the ester prodrug. Based on in vitro results, the risk of a clinically significant drug-drug interaction with ethanol is anticipated to be low.

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Carboxylesterase 1 Polymorphism Impairs Oseltamivir Bioactivation in Humans

Cited by 67 publications

References 17 publications

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

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

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

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

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