The effect of carboxylesterase 1 (CES1) polymorphisms on the pharmacokinetics of oseltamivir in humans

Suzaki, Yuki; Uemura, Naoto; Takada, Makoto; Ohyama, Tetsuji; Itohda, Akiko; Morimoto, Takahiro; Imai, Hiromitsu; Hamasaki, Hajime; Inano, Akihiro; Hosokawa, Masakiyo; Tateishi, Masato; Ohashi, Kyoichi

doi:10.1007/s00228-012-1315-5

Cited by 30 publications

(29 citation statements)

References 27 publications

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“…CES enzymes hydrolyze diverse xenobiotic and endogenous substrates that contain carboxylic acid esters, carbamates, thioesters, and amide compounds. [1][2][3][4] Two major subfamilies of identified CES are human carboxylesterase 1 (CES1) and human carboxylesterase 2 (CES2). [2,4] CES1 gene is located on chromosome 16q13-q22.1 and contains 14 exons.…”

Section: Introductionmentioning

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: Introductionmentioning

confidence: 99%

“…[2,4] CES1 gene is located on chromosome 16q13-q22.1 and contains 14 exons. [3,5] To date (29-Apr-2014), a total of 1107 single nucleotide polymorphisms (SNPs) in CES1 have been documented in the NCBI SNP database (http://www.ncbi. nlm.nih.gov).…”

Section: Introductionmentioning

confidence: 99%

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

Jung

Jeong

Shin

et al. 2014

Transl Clin Pharmacol

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“…CES1 has been previously biochemically characterized as an oseltamivir-activating enzyme, yet human CES1 polymorphisms do not account for all of the variability in patient prodrug activation 27 . Under the background of this model, we sought to establish if substrate-competitive activity-based profiling could directly annotate oseltamivir-activating enzymes among serine hydrolases present in human Caco-2 cell homogenates, a cell line that expresses multiple carboxylesterases 28 and is widely used for modeling human intestinal absorption 29 .…”

Section: Substrate-competitive Profiling Of Oseltamivir-binding Serinmentioning

confidence: 99%

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

Martin

2018

Drug Metabolism and Pharmacokinetics

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Understanding the mechanistic basis of prodrug delivery and activation is critical for establishing species-specific prodrug sensitivities necessary for evaluating pre-clinical animal models and potential drug-drug interactions. Despite significant adoption of prodrug methodologies for enhanced pharmacokinetics, functional annotation of prodrug activating enzymes is laborious and often unaddressed. Activity-based protein profiling (ABPP) describes an emerging chemoproteomic approach to assay active site occupancy within a mechanistically similar enzyme class in native proteomes. The serine hydrolase enzyme family is broadly reactive with reporterlinked fluorophosphonates, which have shown to provide a mechanism-based covalent labeling strategy to assay the activation state and active site occupancy of cellular serine amidases, esterases, and thioesterases. Here we describe a modified ABPP approach using direct substrate competition to identify activating enzymes for an ethyl ester prodrug, the influenza neuraminidase inhibitor oseltamivir. Substrate-competitive ABPP analysis identified carboxylesterase 1 (CES1) as an oseltamivir-activating enzyme in intestinal cell homogenates. Saturating concentrations of oseltamivir lead to a 4-fold reduction in the observed rate constant for CES1 inactivation by fluorophosphonates. WWL50, a reported carbamate inhibitor of mouse CES1, blocked oseltamivir hydrolysis activity in human cell homogenates, confirming CES1 is the primary prodrug activating enzyme for oseltamivir in human liver and intestinal cell lines. The related carbamate inhibitor WWL79 inhibited mouse, but not human CES1, providing a series of probes for analyzing prodrug activation mechanisms in different preclinical models. Overall, we present a substratecompetitive activity-based profiling approach for broadly surveying candidate prodrug hydrolyzing enzymes and outline the kinetic parameters for activating enzyme discovery, ester prodrug design and preclinical development of ester prodrugs. HHS Public Access

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“…The formation of sacubitrilat from sacubitril is mediated by carboxylesterase 1, an enzyme which is shown to have distinct ethnic differences based on genetic polymorphisms and haplotype frequencies [96]. However, these differences did not impact its activity, measured as the ratio of oseltamivir carboxylate/oseltamivir, a carboxylesterase 1-mediated conversion [97]. Our pooled analysis, which revealed no clinically relevant impact of race and ethnicity on pharmacokinetics of sacubitril and sacubitrilat, also suggested that carboxylesterase 1 polymorphisms are unlikely to affect the conversion of sacubitril to sacubitrilat.…”

Section: Race/ethnicitymentioning

confidence: 99%

Erratum to: Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor–Neprilysin Inhibitor

et al. 2017

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Sacubitril/valsartan (LCZ696) is indicated for the treatment of heart failure with reduced ejection fraction. Absorption of sacubitril/valsartan and conversion of sacubitril (prodrug) to sacubitrilat (neprilysin inhibitor) was rapid with maximum plasma concentrations of sacubitril, sacubitrilat, and valsartan (angiotensin receptor blocker) reaching within 0.5, 1.5-2.0, and 2.0-3.0 h, respectively. With a twofold increase in dose, an increase in the area under the plasma concentration-time curve was proportional for sacubitril, *1.9-fold for sacubitrilat, and *1.7-fold for valsartan in healthy subjects. Following multiple twice-daily administration, steady-state maximum plasma concentration was reached within 3 days, showing no accumulation for sacubitril and valsartan, while *1.6-fold accumulation for sacubitrilat. Sacubitril is eliminated predominantly as sacubitrilat through the kidney; valsartan is eliminated mainly by biliary route. Drug-drug interactions of sacubitril/valsartan were evaluated with medications commonly used in patients with heart failure including furosemide, warfarin, digoxin, carvedilol, levonorgestrel/ethinyl estradiol combination, amlodipine, omeprazole, hydrochlorothiazide, intravenous nitrates, metformin, statins, and sildenafil. Co-administration with sacubitril/valsartan increased the maximum plasma concentration (*2.0-fold) and area under the plasma concentration-time curve (1.3-fold) of atorvastatin; however, it did not affect the pharmacokinetics of simvastatin. Age, sex, or ethnicity did not affect the pharmacokinetics of sacubitril/valsartan. In patients with heart failure vs. healthy subjects, area under the plasma concentration-time curves of sacubitril, sacubitrilat, and valsartan were higher by approximately 1.6-, 2.1-, and 2.3-fold, respectively. Renal impairment had no significant impact on sacubitril and valsartan area under the plasma concentration-time curves, while the area under the plasma concentrationtime curve of sacubitrilat correlated with degree of renal function (1.3-, 2.3-, 2.9-, and 3.3-fold with mild, moderate, and severe renal impairment, and end-stage renal disease, respectively). Moderate hepatic impairment increased the area under the plasma concentration-time curves of valsartan and sacubitrilat *2.1-fold.The in-text citations in the tables were misaligned with the references in the original article. The full article with all the corrections is republished here.The online version of the original article can be found under

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The effect of carboxylesterase 1 (CES1) polymorphisms on the pharmacokinetics of oseltamivir in humans

Cited by 30 publications

References 27 publications

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

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

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

Erratum to: Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor–Neprilysin Inhibitor

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