Physiologically Based Pharmacokinetic Modeling of Impaired Carboxylesterase-1 Activity: Effects on Oseltamivir Disposition

  title={Physiologically Based Pharmacokinetic Modeling of Impaired Carboxylesterase-1 Activity: Effects on Oseltamivir Disposition},
  author={Zhe-yi Hu and A. Edginton and S. Laizure and R. B. Parker},
  journal={Clinical Pharmacokinetics},
Background and ObjectiveHuman carboxylesterase-1 (CES1) is an enzyme that is primarily expressed in the liver, where it plays an important role in the metabolism of many commonly used medications. Ethanol (alcohol)-mediated inhibition of CES1 and loss-of-function polymorphisms in the CES1 gene can markedly reduce this enzyme’s function. Such alterations in CES1 activity may have important effects on the disposition of substrate drugs. The aim of this study is to develop a physiologically based… Expand
Carboxylesterase 1 and Precision Pharmacotherapy: Pharmacogenetics and Nongenetic Regulators
Predicting the hepatic CES1 function can provide clinical guidance to optimize pharmacotherapy of numerous medications metabolized by CES1, and genetic polymorphisms, including single-nucleotide polymorphisms and copy number variants and nongenetic contributors, that could influence CES1 functionality and the PK and PD of CES1 substrates are discussed. Expand
Age-Dependent Absolute Abundance of Hepatic Carboxylesterases (CES1 and CES2) by LC-MS/MS Proteomics: Application to PBPK Modeling of Oseltamivir In Vivo Pharmacokinetics in Infants
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Physiologically Based Pharmacokinetic ( PBPK ) Modeling and Simulation Approaches : A Systematic Review of Published Models , Applications , and Model Verification s
Modeling and simulation of drug disposition has emerged as an important tool in drug development, clinical study design and regulatory review, and the number of physiologically based pharmacokineticExpand
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Ethanol Interactions With Dexmethylphenidate and dl-Methylphenidate Spheroidal Oral Drug Absorption Systems in Healthy Volunteers
These findings support drug dispositional interactions between ethanol and MPH as dominant over potential biopharmaceutical considerations and Understanding the pharmacology underlying the frequent coabuse of MPH-ethanol provides rational guidance in the selection of first-line pharmacotherapy for comorbid attention-deficit/hyperactivity disorder–alcohol use disorder. Expand
Highly sensitive and selective detection of human carboxylesterase 1 activity by liquid chromatography with fluorescence detection.
  • D. Wang, Q. Jin, +8 authors L. Yang
  • Chemistry, Medicine
  • Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
  • 2016
The newly developed LC-FD method was successfully applied to measure hCE1 activity in human liver preparations from individual donors (n=12), as well as in homogenates from eleven different human cell lines, which are very helpful for the deep understanding of the expression and function of h CE1 in human biological samples. Expand


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Clopidogrel pharmacotherapy is associated with substantial interindividual variability in clinical response, which can translate into an increased risk of adverse outcomes. Clopidogrel, a recognizedExpand
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Evaluation of the inhibitory effects of antihypertensive drugs on human carboxylesterase in vitro.
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Development of a Physiologically Based Model for Oseltamivir and Simulation of Pharmacokinetics in Neonates and Infants
Simulations showed agreement with a wide range of observational data, indicating that the processes determining the age-dependent pharmacokinetics of oseltamivir are well described, and exemplifies the utility of PBPK models in predicting pharmacokinetic in the very young. Expand
The Role of Human Carboxylesterases in Drug Metabolism: Have We Overlooked Their Importance?
Evidence exists that genetic polymorphisms, drug‐drug interactions, drug-disease interactions and other factors are important determinants of the variability in the therapeutic response to carboxylesterase‐substrate drugs. Expand
Towards Quantitation of the Effects of Renal Impairment and Probenecid Inhibition on Kidney Uptake and Efflux Transporters, Using Physiologically Based Pharmacokinetic Modelling and Simulations
Background and ObjectivesThe kidney is a major drug-eliminating organ. Renal impairment or concomitant use of transporter inhibitors may decrease active secretion and increase exposure to a drug thatExpand
Carboxylesterase 1 Polymorphism Impairs Oseltamivir Bioactivation in Humans
A pharmacokinetic study with 75 mg oseltamivir was carried out in c.428G>A carriers and noncarriers, and it is shown that the CES1 c. Expand
Inhibition of human carboxylesterases hCE1 and hiCE by cholinesterase inhibitors.
Inhibition of hCE1 and hiCE by carbamate-containing small molecules, including those used for the treatment of Alzheimer's disease, is observed and the administration of esterified drugs, in combination with these carbamates, may inadvertently result in decreased hydrolysis of the former, thereby limiting their efficacy. Expand
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