Assessing Human Interindividual Differences in Chemical Metabolism As Mediators of Risk. J. C. Lipscomb, U.S. EPA/NCEA, Cincinnati, OH; J. E. Seng, U.S. FDA/NCTR, Jefferson, AR; and J. E. Snawder, CDC/NIOSH, Cincinnati, OH
Quantification of human interindividual variability (IV) in pharmacokinetics (PK) can aid the understanding susceptibility and refine the human IV uncertainty factor (UFH) by characterizing the magnitude of its pharmacokinetic and pharmacodynamic (PD) components. This has been done for the laboratory animal to human uncertainty factor (UFA) by various regulatory agencies. Quantification of human interindividual variability (IV) in pharmacokinetics (PK) can aid the understanding susceptibility and refine the human IV uncertainty factor (UFH) by characterizing the magnitude of its pharmacokinetic and pharmacodynamic (PD) components. This has been done for the laboratory animal to human uncertainty factor (UFA) by various regulatory agencies. TCE’s in vitro metabolism is significantly positively correlated with CYP2E1 activity and CYP2E1 protein. Metabolic rates (n=23) were extrapolated, based on protein recovery, to 6.9 mg/hr/kg and used in physiologically based PK models to assess the IV of TCE’s PK. Model predictions (of others) in the absence of in vitro data were 4 to 15 mg/hr/kg. Human IV was measured for markers of activities for 7 CYP forms in 130 human samples, indicating standard deviations of 46 to 111% of mean values and a normal distribution. CYP2E1 activity demonstrated a mean value of 1090 (range 242 to 3635; S.D. 566) pmol/min/mg protein. Use of these values can lead to model predictions of population PK variability which may be used to determine the appropriate magnitude of the UFH PK component.
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