METABOLISM AND PHARMACOKINETIC PROFILE OF VINYLIDENE-CHLORIDE IN RATS FOLLOWING ORAL-ADMINISTRATION

Male rats (normally fed or previously fasted for 18 hr) were given a single oral dose of 1 or 50 mg/kg of [14C]vinylidene chloride (VDC) in corn oil and the routes and rates of elimination of 14C activity were then followed for 72 hr. After a single oral dose of 1 mg/kg of [14C]VDC, 78% of the dose was metabolized and excreted in urine and feces as nonvolatile metabolites of VDC. The remainder was exhaled as 14CO2 (21%) and unchanged [14C]VDC (1-3%). Fasting prior to [14C]VDC administration did not significantly affect the fate of the 1-mg/kg dose of [14C]VDC. Conversely, after a 50-mg/kg dose of [14C]VDC, excretion of the parent compound via the lungs accounted for 19 and 29% of the dose in fed and fasted rats, respectively. Elimination of nonvolatile metabolites of VDC was slightly greater in fed than in fasted rats indicating a reduced capacity for metabolism of VDC in fasted rats. Fasting also resulted in an increased concentration of covalently bound [14C]VDC metabolites in the livers of rats given 50 mg/kg of [14C]VDC. Urinary radioactivity was separated by high-pressure liquid chromatography into four major metabolites. Two of the four urinary metabolites were identified as S-(2-hydroxyethyl)-N-acetylcysteine and thiodiglycolic acid by gas chromatography-mass spectrometry, indicating that a major pathway for detoxification of VDC is via conjugation with glutathione (GSH). The fate of VDC following oral administration to rats is depedent upon both the dose administered and the nutritional status of the animal. The diminished ability of fasted animals to metabolize the high dose of VDC correlates well with the previously observed enhancement of VDC-induced hepatotoxicity in fasted animals. Both the hepatotoxic response to VDC and the extent of its detoxification appear to be dependent on the concentration of GSH in the liver. When hepatic GSH is depleted (i.e., in fasted animals or at higher doses of VDC) a toxic response to VDC is elicited. © 1978.