The impact of XXXX -dependent metabolic variance on a risk-relevant pharmacokinetic outcome in @entity1 .

@entity1 @entity4966 @entity99 @entity4965 @entity130 @entity5321
Risk assessments include assumptions about sensitive subpopulations, such as the fraction of the general population that is sensitive and the extent that biochemical or physiological attributes influence sensitivity. Uncertainty factors (UF) account for both pharmacokinetic (PK) and pharmacodynamic (PD) components, allowing the inclusion of risk-relevant information to replace default assumptions about PK and PD variance (uncertainty). Large numbers of @entity1 organ donor samples and recent advances in methods to extrapolate in vitro enzyme expression and activity data to the intact @entity1 enable the investigation of the impact of PK variability on @entity1 susceptibility. The hepatotoxicity of @entity4965 ( @entity4966 ) is mediated by acid metabolites formed by @entity5321 ( @entity5321 ) oxidation, and differences in the @entity5321 expression are hypothesized to affect susceptibility to @entity4966 's @entity99 . This study was designed specifically to examine the contribution of statistically quantified variance in enzyme content and activity on the risk of @entity130 among adult @entity1 . We combined data sets describing (1) the microsomal protein content of @entity1 liver, (2) the @entity5321 content of @entity1 liver microsomal protein, and (3) the in vitro Vmax for @entity4966 oxidation by @entity1 . The 5th and 95th percentiles of the resulting distribution ( @entity4966 oxidized per minute per gram liver) differed by approximately sixfold. These values were converted to mg @entity4966 oxidized/h/kg body mass and incorporated in a @entity1 PBPK model. Simulations of 8-hour inhalation exposure to 50 ppm and oral exposure to 5 micro g @entity4966 /L in 2 L drinking water showed that the amount of @entity4966 oxidized in the liver differs by 2% or less under extreme values of @entity5321 expression and activity (here, selected as the 5th and 95th percentiles of the resulting distribution). This indicates that differences in enzyme expression and @entity4966 oxidation among the central 90% of the adult @entity1 population account for approximately 2% of the difference in production of the risk-relevant PK outcome for @entity4966 -mediated @entity99 . Integration of in vitro metabolism information into physiological models may reduce the uncertainties associated with risk contributions of differences in enzyme expression and the UF that represent PK variability.
