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• W1985186601 endingPage "1656" @default.
• W1985186601 startingPage "1633" @default.
• W1985186601 abstract "Human variability in the kinetics of CYP2D6 substrates has been quantified using a database of compounds metabolised extensively (>60%) by this polymorphic enzyme. Published pharmacokinetic studies (after oral and intravenous dosing) in non-phenotyped healthy adults, and phenotyped extensive (EMs), intermediate or slow-extensive (SEMs) and poor metabolisers (PMs) have been analysed using data for parameters that relate primarily to chronic exposure (metabolic and total clearances, area under the plasma concentration time-curve) and primarily to acute exposure (peak concentration). Similar analyses were performed with the available data for subgroups of the population (age, ethnicity and disease). Interindividual differences in kinetics for markers of oral exposure were large for non-phenotyped individuals and for EMs (coefficients of variation were 67-71% for clearances and 54-63% for C(max)), whereas the intravenous data indicated a lower variability (34-38%). Comparisons between EMs, SEMs and PMs revealed an increase in oral internal dose for SEMs and PMs (ratio compared to EMs=3 and 9-12, respectively) associated with lower variability than that for non-phenotyped individuals (coefficients of variation were 32-38% and 30% for SEMs and PMs, respectively). In relation to the uncertainty factors used for risk assessment, most subgroups would not be covered by the kinetic default of 3.16. CYP2D6-related factors necessary to cover 95-99% of each subpopulation ranged from 2.7 to 4.1 in non-phenotyped healthy adults and EMs to 15-18 in PMs and 22-45 in children. An exponential relationship (R(2)=0.8) was found between the extent of CYP2D6 metabolism and the uncertainty factors. The extent of CYP2D6 involvement in the metabolism of a substrate is critical in the estimation of the CYP2D6-related factor. The 3.16 kinetic default factor would cover PMs for substrates for which CYP2D6 was responsible for up to 25% of the metabolism in EMs." @default.
• W1985186601 created "2016-06-24" @default.
• W1985186601 creator A5046324513 @default.
• W1985186601 creator A5048004618 @default.
• W1985186601 creator A5052423999 @default.
• W1985186601 creator A5078234115 @default.
• W1985186601 date "2002-11-01" @default.
• W1985186601 modified "2023-10-16" @default.
• W1985186601 title "Human variability in polymorphic CYP2D6 metabolism: is the kinetic default uncertainty factor adequate?" @default.
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