IN VITRO HEPATIC METABOLISM OF PCBTF: DEVELOPMENT OF Vmax AND Km VALUES AND PARTITION COEFFICIENTS AND THEIR USE IN AN INHALATION PBPK MODEL

Abstract

This study was conducted to develop a physiologically based pharmacokinetic (PBPK) model for inhaled p -chlorobenzotrifluoride (PCBTF) for purposes of extrapolating pharmacokinetic and liver hypertrophy data developed by Newton et al. in a 13-wk inhalation neurotoxicity study to humans. Vmax and Km values for the metabolism of PCBTF to 3-OH PCBTF were determined using liver microsomes harvested from female rats previously exposed to 0, 10, 50, and 250 ppm PCBTF by Newton et al. PCBTF tissue partition 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 evidenced 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 significantly alter Vmax (1038 nmol/ h/kg body weight) or Km (65.7 mumol/ L) values for the metabolism of PCBTF to 3-OH PCBTF or change blood concentrations. Human area under the curve (AUC) values for liver and brain (micromoles per liter hour) were found to be less than those of the rat (50 ppm) for 1-day and 13-wk simulations.