Human Variability in Carboxylesterases and carboxylesterase-related Uncertainty Factors for Chemical Risk Assessment
| Autor: | Emanuela Testai, Laura Turco, K. Darney, Susanna Vichi, E. Di Consiglio, Franca M. Buratti, Jean-Lou Dorne, Leonie S. Lautz |
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| Přispěvatelé: | Istituto Superiore di Sanita [Rome], Direction de l'Evaluation des Risques (DER), Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Wageningen Univ & Res, RIKILT, Akkermaalsbos 2, NL-6708 WB Wageningen, Netherlands, Partenaires INRAE, European Food Safety Authority (EFSA), EFSA, Contract number: GP/EFSA/SCER/2015/01 |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Novel Foods & Agrochains [SDV]Life Sciences [q-bio] Pharmacology MESH: Protein Isoforms Toxicology Novel Foods & Agroketens MESH: Risk Assessment 030226 pharmacology & pharmacy human pharmacokinetics Carboxylesterase 0302 clinical medicine Polymorphism (computer science) Protein Isoforms BU Toxicology Novel Foods & Agrochains MESH: Carboxylesterase 0303 health sciences Chemistry BU Toxicology Uncertainty General Medicine Middle Aged Healthy Volunteers Human variability BU Toxicologie Novel Foods & Agroketens Female MESH: Uncertainty medicine.drug Adult Adolescent BU Toxicologie MESH: Environmental Exposure Cmax Team Toxicology CYP2C19 Risk Assessment Dabigatran 03 medical and health sciences Young Adult Pharmacokinetics In vivo medicine Humans 030304 developmental biology Aged variability chemical risk assessment Bayes Theorem Environmental Exposure carboxylesterase MESH: Carboxylic Ester Hydrolases Carboxylic Ester Hydrolases uncertainty factors |
| Zdroj: | Toxicology Letters Toxicology Letters, Elsevier, 2021, 350, pp.162-170. ⟨10.1016/j.toxlet.2021.07.005⟩ Toxicology Letters, 350, 162-170 Toxicology Letters 350 (2021) |
| ISSN: | 0378-4274 |
| DOI: | 10.1016/j.toxlet.2021.07.005⟩ |
| Popis: | International audience; Carboxylesterases (CES) are an important class of enzymes involved in the hydrolysis of a range of chemicals and show large inter-individual variability in vitro. An extensive literature search was performed to identify in vivo probe substrates for CES1 and CES2 together with their protein content and enzymatic activity. Human pharmacokinetic (PK) data on Cmax, clearance, and AUC were extracted from 89 publications and Bayesian meta-analysis was performed using a hierarchical model to derive CES-related variability distributions and related uncertainty factors (UF). The CES-related variability indicated that 97.5% of healthy adults are covered by the kinetic default UF (3.16), except for clopidogrel and dabigatran etexilate. Clopidogrel is metabolised for a small amount by the polymorphic CYP2C19, which can have an impact on the overall pharmacokinetics, while the variability seen for dabigatran etexilate might be due to differences in the absorption, since this can be influenced by food intake. The overall CES-related variability was moderate to high in vivo ( |
| Databáze: | OpenAIRE |
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