Human variability in CYP3A4 metabolism and CYP3A4-related uncertainty factors for risk assessment.
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.
Dorne
J L C M
JL
Clinical Pharmacology Group, University of Southampton, Biomedical Sciences Building, Bassett Crescent East, Southampton SO16 7PX, UK.
Walton
K
K
Renwick
A G
AG
D000328:Adult; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000145:classification / Q000235:genetics*; D019992:Databases as Topic; D004333:Drug Administration Routes; D014644:Genetic Variation; D006801:Humans; D007527:Isoenzymes; D015203:Reproducibility of Results; D018570:Risk Assessment; D035501:Uncertainty; D015262:Xenobiotics / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*
D007527:Isoenzymes; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human