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

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 (C(max)). 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.