Studies on the effects of l-ascorbic acid on acetaminophen-induced hepatotoxicity: II. An in vivo assessment in mice of the protection afforded by various dosage forms of ascorbate

The protection provided by various forms of ascorbate, in several dosage regimens, against acetaminophen (APAP)-induced hepatotoxicity was assessed in male MF1 mice. Hepatotoxicity was produced by treatment with 450 mg APAP/kg po and evaluated 24 hr later by the change in liver weight to body weight ratio and from a histological score of liver necrosis. All treatments were given by gavage in 0.5% tragacanth at 20 ml/kg. No significant protection was given by l-ascorbic acid (LAA) at 50, 150, or 300 mg/kg given at the same time as APAP, nor at 150 or 300 mg/kg given 1 hr afterward. A dose of 150 mg LAA/kg at the same time as, and 2 hr after APAP also failed to give protection. In contrast, other dosage forms showed a protective action. Ascorbyl palmitate provided significant protection at 300 mg/kg. After 600 and 900 mg/kg doses, the liver weight/body weight ratio and necrosis scores were not significantly greater than those in the vehicle controls. The degree of protection by a microencapsulated LAA preparation (MEAA) was related to the fate of the microcapsules in the gastrointestinal tract. This finding suggests that the pharmacokinetic profile of LAA, relative to the time scale of the hepatotoxic processes, may be critical. Sodium ascorbate gave no protection when used in combination with MEAA. The results indicate that ascorbic acid in certain biopharmaceutical forms may have potential use in the development of a safer dosage form of APAP.