Gastrointestinal metabolism of N‐acetylcysteine in the rat, including an assay for sulfite in biological systems

Abstract

The intestinal metabolism of N-acetylcysteine was studied in the rat. Isolated intestinal epithelial cells were shown to rapidly deacetylate [14C]-N-acetylcysteine to [14C]-cysteine, with slight oxidation of the latter to disulfide species. The cells did not accumulate reduced or oxidized cysteine, and N-acetylcysteine itself was not detected either free or in oxidized species intracellularly. Further metabolism of this NAC-derived cysteine to inorganic sulfite or glutathione was not detected. Following the administration of [14C]-N-acetylcysteine (50 mg/kg; 25 microCi) in vivo into the ilium, small quantities of both reduced and oxidized [14C]-N-acetylcysteine were demonstrated in hepatic portal vein plasma. [14C]-cysteine and inorganic sulfite were demonstrated as the major metabolites of N-acetylcysteine. These were present in the portal vein plasma at levels five and three times greater than the parent drug, respectively, 30 min after dosing. Additionally, [14C]-glutathione was shown to be a minor metabolite of N-acetylcysteine accumulating in portal vein plasma. These results may provide an explanation for the apparent low bioavailability of N-acetylcysteine when administered orally in humans and are discussed in terms of the origins of the protective effect of the drug in cases of paracetamol intoxication in humans.