Sensitivity analysis for physiologically based pharmacokinetic models.
The present study evaluates the sensitivity of pharmacokinetic model output to variability in the biochemical and metabolic input parameters. Pharmacokinetic models of three chemicals are chosen for analysis: styrene, methylchloroform, and methylene chloride. Results show that model sensitivities are time-, dose-, and species-dependent and that the most sensitive parameters are the maximum Michaelis-Menten metabolism rate Vmax and the blood/air and fat/air partition coefficients. For humans, the muscle/air partition coefficient is also important. Model output is insensitive to the Michaelis-Menten parameter Km (except for low doses) and to other tissue/air partition coefficients.
Hetrick
D M
DM
Computing and Telecommunications Division, Oak Ridge National Laboratory, Tennessee 37831.
Jarabek
A M
AM
Travis
C C
CC
D000280:Administration, Inhalation; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006801:Humans; D008752:Methylene Chloride / Q000737:chemistry / Q000493:pharmacokinetics; D008954:Models, Biological; D009010:Monte Carlo Method; D010599:Pharmacokinetics; D051381:Rats; D013045:Species Specificity; D013223:Statistics as Topic; D013343:Styrenes / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014240:Trichloroethanes / Q000737:chemistry / Q000493:pharmacokinetics
D013343:Styrenes; D014240:Trichloroethanes; C024566:1,1,1-trichloroethane; D008752:Methylene Chloride