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

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