IN-VITRO HEPATIC-METABOLISM OF PCBTF - DEVELOPMENT OF V-MAX AND K-M VALUES AND PARTITION-COEFFICIENTS AND THEIR USE IN AN INHALATION PBPK MODEL

This study was conducted to develop a physiologically based pharmacoki netic (PBPK) model for inhaled p-chlorobenzotrifluoride (PCBTF) for pu rposes of extrapolating pharmacokinetic and liver hypertrophy data dev eloped by Newton et al. in a 13-wk inhalation neurotoxicity study to h umans. V-max and K-m values for the metabolism of PCBTF to 3-OH PCBTF were determined using liver microsomes harvested from female rats prev iously exposed to 0, 10, 50, and 250 ppm PCBTF by Newton et al. PCBTF tissue par tition coefficients were developed using published methods and tissues from control animals. Work by Newton et al, suggested that 13 wk of exposure to PCBTF induced rat cytochrome P-450 activity as e videnced by liver hepatocyte hypertrophy (NOEL, 50 ppm) and a decrease in PCBTF concentrations in blood during the study. The present study showed that exposure to PCBTF (0, 10, 50, and 250 ppm) did not signifi cantly alter V-max (1038 nmol/h/kg body weight) or K-m (65.7 mu mol/L) values for-the metabolism of PCBTF to 3-OH PCBTF or change blood conc entrations. Human area under the curve (AUC) values for liver and brai n (micromoles per liter hour) were found to be less than those of the rat (50 ppm) for 1-day and 13-wk simulations.