Human variability in kinetics for the major metabolic pathways : Application to chemical risk assessment

Abstract

This thesis deals with the statistical analysis of human variability in kinetics for the major metabolic pathways (Phase I (CYP isoforms (CYP1A2, CYP2C9, CYP2C19 CYP2D6, CYP2E1, CYP3A4), hydrolysis, Alcohol dehydrogenase). Phase n (N-acetyltransferases, glucuronidation, glycine conjugation, sulphation) and renal excretion) to investigate the appropriateness of the default uncertainty factor (10°^ 3.16) currently in use for the risk assessment of thresholded toxicants and accounting for human variability in kinetics. Probe substrates were selected on the basis that oral absorption was total and that the metabolic route was the primary route of elimination of the compound (60-100% of an oral). Intravenous data were used for compounds for which absorption was variable. Human variability in kinetics was quantified for each compound from published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and other subgroups of the population (effect of ethnicity, age and disease) using parameters relating to chronic exposure (metabolic and total clearances, area under the plasma concentration time-curve (AUG)) and acute exposure (Cmax). All parameters were analysed using the assumptions that data were either normally or log normally distributed and that kinetics were linear. Three sets of pathway-related uncertainty factors were calculated using the lognormal variability in kinetics to cover 95^, 97.5^ and 99"^ centile of the general healthy adult population respectively. These pathway-related uncertainty factors were also calculated for subgroups using the magnitude of the difference in internal dose between each subgroup and healthy adults (ratio of geometric means and the subgroup specific variability). Low inter-individual variability (about 21-31%) and pathway-related uncertainty factors (1.6- 2.2, 99*^ centile) were found for all monomorphic pathways with the exception of CYP3A4 metabolism for which variability after oral dosing was 46% (2.8, 99"^ centile). Polymorphic pathways showed that the current kinetic default would not be adequate to cover healthy adult poor metabolisers for CYP2D6 and CYP2C19 metabolism and slow acetylators for N-acetylation and uncertainty factors of 26, 52 and 5.2 would cover these

More information

Identifiers

Catalogue record

Export record

ASCII CitationAtomBibTeXData Cite XMLDublin CoreDublin CoreEP3 XMLEndNoteHTML CitationHTML CitationHTML ListJSONMETSMODSMPEG-21 DIDLOpenURL ContextObjectOpenURL ContextObject in SpanRDF+N-TriplesRDF+N3RDF+XMLRIOXX2 XMLReferReference ManagerSimple Metadata