COMPARATIVE METABOLISM OF CARBON TETRACHLORIDE IN RATS, MICE, AND HAMSTERS USING GAS UPTAKE AND PBPK MODELING.

No study has comprehensively compared the rate of metabolism of carbon tetrachloride (CCl[sub 4]) across species. Therefore, the in vivo metabolism of CCl[sub 4] was evaluated using groups of male animals (F344 rats, B6C3F[sub 1] mice, and Syrian hamsters) exposed to 40-1800 ppm CCl[sub 4] in a closed, recirculating gas-uptake system. For each species, an optimal fit of the family of uptake curves was obtained by adjusting Michaelis-Menten metabolic constants K [sub m] (affinity) and V [sub max] (capacity) using a physiologically based pharmacokinetic (PBPK) model. The results show that the mouse has a slightly higher capacity and lower affinity for metabolizing CCl[sub 4] compared to the rat, while the hamster has a higher capacity and lower affinity than either rat or mouse. A comparison of the V [sub max] to K [sub m] ratio, normalized for milligrams of liver protein (L/ h/ mg) across species, indicates that hamsters metabolize more CCl[sub 4] than either rats or mice, and should be more susceptible to CCl[sub 4]-induced hepatotoxicity. These species comparisons were evaluated against toxicokinetic studies conducted in animals exposed by nose-only inhalation to 20 ppm 14C-labeled CCl[sub 4] for 4 h. The toxicokinetic study results are consistent with the in vivo rates of metabolism, with rats eliminating less radioactivity associated with metabolism ( 14CO [sub 2] and urine/ feces) and more radioactivity associated with the parent compound (radioactivity trapped on charcoal) compared to either hamsters or mice. The in vivo metabolic constants determined here, together with in vitro constants determined using rat, mouse, hamster, and human liver microsomes, were used to estimate human in vivo metabolic rates of 1.49 mg/ h/ kg body weight and 0.25 mg/ L for V [sub max] and K [sub m], respectively. Normalizing the rate of metabolism ( V [sub ma] / K [sub m]) by milligrams liver protein, the rate of metabolism of CCl[sub 4] differs across species, with[sup x]hamster > mouse > rat > human. [ABSTRACT FROM AUTHOR]