Human Variability in Carboxylesterases and carboxylesterase-related Uncertainty Factors for Chemical Risk Assessment

Area of Science:

• Pharmacology
• Enzymology
• Drug Metabolism

Background:

• Carboxylesterases (CES) are crucial enzymes for chemical hydrolysis.
• Significant inter-individual variability in CES activity is observed in vitro.
• Understanding in vivo variability is essential for accurate pharmacokinetic modeling.

Purpose of the Study:

• To identify in vivo probe substrates for CES1 and CES2.
• To quantify CES-related variability in human pharmacokinetics (PK).
• To derive CES-related variability distributions and uncertainty factors (UF).

Main Methods:

• Extensive literature search for CES probe substrates and PK data.
• Extraction of pharmacokinetic data (Cmax, clearance, AUC) from 89 publications.
• Bayesian meta-analysis using a hierarchical model to determine variability.

Main Results:

• CES-related variability generally falls within the default UF (3.16) for 97.5% of healthy adults.
• Exceptions include clopidogrel (affected by CYP2C19 polymorphism) and dabigatran etexilate (potential absorption variability).
• In vivo CES variability is moderate to high (

Conclusions:

• The derived CES-related variability distributions can inform pathway-specific PK modeling.
• The findings highlight specific drug PK influenced by CES variability.
• Further research may be needed to address variability in specific drug substrates and enzyme polymorphism.