Human variability in CYP3A4 metabolism and CYP3A4-related uncertainty factors for risk assessment


Dorne, J.L.C.M., Walton, K. and Renwick, A.G. (2003) Human variability in CYP3A4 metabolism and CYP3A4-related uncertainty factors for risk assessment. Food and Chemical Toxicology, 41, (2), 201-224. (doi:10.1016/S0278-6915(02)00209-0).

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Description/Abstract

CYP3A4 constitutes the major liver cytochrome P450 isoenzyme and is responsible for the oxidation of more than 50% of all known drugs. Human variability in kinetics for this pathway has been quantified using a database of 15 compounds metabolised extensively (>60%) by this CYP isoform in order to develop CYP3A4-related uncertainty factors for the risk assessment of environmental contaminants handled via this route.

Data were analysed from published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and other subgroups using parameters relating primarily to chronic exposure [metabolic and total clearances, area under the plasma concentration–time curve (AUC)] and acute exposure (Cmax). Interindividual variability in kinetics was greater for the oral route (46%, 12 compounds) than for the intravenous route (32%, 14 compounds). The physiological and molecular basis for the difference between these two routes of exposure is discussed. In relation to the uncertainty factors used for risk assessment, the default kinetic factor of 3.16 would be adequate for adults, whereas a CYP3A4-related factor of 12 would be required to cover up to 99% of neonates, which have lower CYP3A4 activity.

Item Type: Article
ISSNs: 0278-6915 (print)
Related URLs:
Keywords: human variability, pharmacokinetics, cyp3a4, uncertainty factors, risk assessment, sensitive subgroups
Subjects: R Medicine > RM Therapeutics. Pharmacology
Q Science > QP Physiology
Divisions: University Structure - Pre August 2011 > School of Medicine > Infection, Inflammation and Repair
ePrint ID: 27030
Date Deposited: 26 Apr 2006
Last Modified: 27 Mar 2014 18:15
Contact Email Address: a.g.renwick@soton.ac.uk
URI: http://eprints.soton.ac.uk/id/eprint/27030

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