Pharmacokinetics and mechanism of action of detoxifying low-molecular-weight thiols.
A number of thiol compounds have been studied with reference to their selective protective action against urotoxic side-effects of oxazaphosphorine cytostatics. The uroprotective capacity is determined exclusively by the pharmacokinetic behavior of the compound. When given PO, all compounds tested were absorbable from the gut. Both thiols and disulfides are rapidly eliminated from the blood, but during their short half-life a number of unknown chemical reactions probably take place to maintain a physiological redox equilibrium. Elimination from the blood plasma occurs via two fundamentally different mechanisms: by distribution throughout the tissues and intracellular uptake or, alternatively, by rapid renal excretion. Most of the compounds tested belong to the first group: N-acetylcysteine, carboxycysteine, disulfiram and its metabolite DDTC, glutathione, WR 2721, etc. Few compounds are quantitatively excreted through the urine: mesna, dimesna, and DA 12. Only these compounds were suitable for selective regional detoxification and for the prevention of oxazaphosphorine-induced urotoxic lesions.
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D007700:Kinetics; D008297:Male; D008970:Molecular Weight; D051381:Rats; D011919:Rats, Inbred Strains; D013438:Sulfhydryl Compounds / Q000378:metabolism* / Q000494:pharmacology; D013455:Sulfur / Q000378:metabolism
D000970:Antineoplastic Agents; D004220:Disulfides; D013438:Sulfhydryl Compounds; D013455:Sulfur