The University of Southampton
University of Southampton Institutional Repository

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

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

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

University of Southampton
Dorne, Jean L.C.M
0936d2d9-1f04-4e3f-88e7-e6cf40e0617c
Dorne, Jean L.C.M
0936d2d9-1f04-4e3f-88e7-e6cf40e0617c

Dorne, Jean L.C.M (2001) Human variability in kinetics for the major metabolic pathways : Application to chemical risk assessment. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

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

Text
841554.pdf - Version of Record
Available under License University of Southampton Thesis Licence.
Download (13MB)

More information

Published date: 2001

Identifiers

Local EPrints ID: 464623
URI: http://eprints.soton.ac.uk/id/eprint/464623
PURE UUID: 9d5a9bc3-fc54-4d9d-9733-7b0c6cbfb7f1

Catalogue record

Date deposited: 04 Jul 2022 23:51
Last modified: 23 Jul 2022 02:13

Export record

Contributors

Author: Jean L.C.M Dorne

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×