Metabolism of [ 14C]carbon tetrachloride to exhaled, excreted and bound metabolites : Dose-response, time-course and pharmacokinetics

Fasted male rats were given six doses of 14CCl 4 ranging from non-hepatotoxic (0.1 mmole/kg) to severely hepatotoxic (26mmoles/kg). Time-course and pharmacokinetics of CCl 4, 14CO 2 and CHCL 3 elimination by exhalation were monitored by measuring amounts recovered in breath during discrete 15-min intervals for 8–12 hr. Amounts of 14C-labeled metabolite recovered bound to liver macromolecules at 24 hr and excreted in urine or feces for 24 hr were also determined. Comparison pharmacokinetic studies were done with 14CHCl 3 and Na 2 14CO 3. After all doses of 14CCl 4, the major metabolite was CO 2, twenty to thirty times less metabolite was recovered bound to liver macromolecules, and intermediate amounts of metabolite were excreted in urine and feces. CHCl 3 was the least abundant metabolite at low CCl 4 doses, but the second most abundant at high doses. Stronger associations were found between the magnitude of liver injury at 24 hr (quantitated as serum glutamate-pyruvate transaminase activity) and the extent or rate of CCl 4 metabolism by pathways leading to CO 2 and CHCl 3 than by pathways leading to 14C-metabolites bound in liver or excreted in urine. Time-course and pharmacokinetic data indicated that a major pathway of CCl 4 metabolism leading to CO 2; became impaired within 2 hr after administration of hepatotoxic doses of CCl 4.