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Human variability for metabolic pathways with limited data (CYP2A6, CYP2C9, CYP2E1, ADH, esterases, glycine and sulphate conjugation)

Human variability for metabolic pathways with limited data (CYP2A6, CYP2C9, CYP2E1, ADH, esterases, glycine and sulphate conjugation)
Human variability for metabolic pathways with limited data (CYP2A6, CYP2C9, CYP2E1, ADH, esterases, glycine and sulphate conjugation)
Human variability in the kinetics of a number of phase I (CYP2A6, CYP2C9, CYP2E1, alcohol dehydrogenase and hydrolysis) and phase II enzymes (glycine and sulphate conjugation) was analysed using probe substrates metabolised extensively (>60%) by these routes. Published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and available data on subgroups of the population (effects of ethnicity, age and disease) were abstracted using parameters relating primarily to chronic exposure [metabolic and total clearances, area under the plasma concentration time-curve (AUC)] and acute exposure (Cmax). Interindividual differences in kinetics for all these pathways were low in healthy adults ranging from 21 to 34%. Pathway-related uncertainty factors to cover the 95th, 97.5th and 99th centiles of healthy adults were derived for each metabolic route and were all below the 3.16 kinetic default uncertainty factor in healthy adults, with the possible exception of CYP2C9*3/*3 poor metabolisers (based on a very limited number of subjects). Previous analyses of other pathways have shown that neonates represent the most susceptible subgroup and this was true also for glycine conjugation for which an uncertainty factor of 29 would be required to cover 99% of this subgroup. Neonatal data were not available for any other pathway analysed.
Abbreviations: CYP Cytochrome P450, AUC Area under the plasma-concentration-time-curve, Cmax Maximum plasma concentration
Human variability, Pharmacokinetics, Phase I metabolism, Phase II metabolism, Uncertainty factors, Risk assessment, Sensitive subgroups
0278-6915
397-421
Dorne, J.L.C.M.
bb24d5c7-c4fd-445a-9785-0a03d216fdc2
Walton, K.
024c9ff2-0a40-4fda-a213-db73d9971871
Renwick, A.G.
596705ab-5418-4e02-9ad7-c4309326df46
Dorne, J.L.C.M.
bb24d5c7-c4fd-445a-9785-0a03d216fdc2
Walton, K.
024c9ff2-0a40-4fda-a213-db73d9971871
Renwick, A.G.
596705ab-5418-4e02-9ad7-c4309326df46

Dorne, J.L.C.M., Walton, K. and Renwick, A.G. (2004) Human variability for metabolic pathways with limited data (CYP2A6, CYP2C9, CYP2E1, ADH, esterases, glycine and sulphate conjugation). Food and Chemical Toxicology, 42 (3), 397-421. (doi:10.1016/j.fct.2003.10.003).

Record type: Article

Abstract

Human variability in the kinetics of a number of phase I (CYP2A6, CYP2C9, CYP2E1, alcohol dehydrogenase and hydrolysis) and phase II enzymes (glycine and sulphate conjugation) was analysed using probe substrates metabolised extensively (>60%) by these routes. Published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and available data on subgroups of the population (effects of ethnicity, age and disease) were abstracted using parameters relating primarily to chronic exposure [metabolic and total clearances, area under the plasma concentration time-curve (AUC)] and acute exposure (Cmax). Interindividual differences in kinetics for all these pathways were low in healthy adults ranging from 21 to 34%. Pathway-related uncertainty factors to cover the 95th, 97.5th and 99th centiles of healthy adults were derived for each metabolic route and were all below the 3.16 kinetic default uncertainty factor in healthy adults, with the possible exception of CYP2C9*3/*3 poor metabolisers (based on a very limited number of subjects). Previous analyses of other pathways have shown that neonates represent the most susceptible subgroup and this was true also for glycine conjugation for which an uncertainty factor of 29 would be required to cover 99% of this subgroup. Neonatal data were not available for any other pathway analysed.
Abbreviations: CYP Cytochrome P450, AUC Area under the plasma-concentration-time-curve, Cmax Maximum plasma concentration

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Published date: 2004
Keywords: Human variability, Pharmacokinetics, Phase I metabolism, Phase II metabolism, Uncertainty factors, Risk assessment, Sensitive subgroups

Identifiers

Local EPrints ID: 27031
URI: https://eprints.soton.ac.uk/id/eprint/27031
ISSN: 0278-6915
PURE UUID: 4ba009a7-67a5-4944-ace4-03d072d93783

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Date deposited: 26 Apr 2006
Last modified: 17 Jul 2017 16:05

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Contributors

Author: J.L.C.M. Dorne
Author: K. Walton
Author: A.G. Renwick

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