PHYSIOLOGICALLY-BASED PHARMACOKINETIC ESTIMATED METABOLIC CONSTANTS AND HEPATOTOXICITY OF CARBON-TETRACHLORIDE AFTER METHANOL PRETREATMENT IN RATS

A single 6-hr exposure to inhaled methanol (MeOH) has been shown to en hance carbon tetrachloride (CCl4) hepatotoxicity. The objective of the present study was to use gas uptake data and the development of a phy siologically based pharmacokinetic model (PBPK) to determine in vivo c hanges in CCl4 metabolism resulting from MeOH pretreatment. Adult male F344 rats (167-197 g) were exposed to 10,000 ppm MeOH (constant conce ntration) via inhalation for 6 hr. Individual rats were exposed using gas uptake techniques to CCl4 alone or to CCl4 either 24 or 48 hr afte r initiation of MeOH pretreatment. The following initial concentration s were used for CCl4: 0, 25, 100, 250, and 1000 ppm with exposures las ting 6 hr, V-max (metabolic rate) was estimated from gas uptake data a nd K-m (Michaelis constant) was assumed constant after methanol pretre atment, For CCl4 alone, V-max was 0.11 mg/hr (V-maxc = 0.37 mg/hr/kg) and K-m was 1.3 g/liter. V-max was 0.48 mg/hr (V-maxc = 1.6 mg/hr/kg) for the 24-hr MeOH +/- CCl4 group and V-max was 0.18 mg/hr (V-maxc = 0 .6 mg/hr/kg) for the 48-hr MeOH + CCl4 group. For CCl4 alone, serum ma rkers of hepatotoxicity alanine aminotransferase (ALT) and sorbitol de hydrogenase (SDH) were increased significantly only at 1000 ppm CCl4. Both serum markers of hepatotoxicity in the 24-hr MeOH + CCl4 group in creased as a function of CCl4 concentration when compared with 0 ppm C Cl4 controls, The maximum increase occurred at 1000 ppm CCl4, where AL T and SDH increased by 392- and 286-fold, respectively. At 100, 250, a nd 1000 ppm CCl4, ALT and SDH values for the 24-hr MeOH + CCl4 groups were significantly increased relative to control (0 ppm CCl4), CCl4 al one, and 48-hr MeOH + CCl4. ALT and SDH levels in the 48-hr MeOH + CCl 4 groups were not statistically different from the respective CCl4 alo ne groups. (C) 1996 Academic Press, Inc.