Misonidazole neurotoxicity in mice decreased by administration with pyridoxine.
A series of toxicological and pharmacological experiments was performed to test the hypothesis that alterations of pyridoxine (Vitamin B6) metabolism may play an important role in the development of misonidazole (MISO) neurotoxicity. The formation of a Schiff's base between the final reduction product of MISO, 2-amino MISO (NH2-MISO), and pyridoxal-HCl in ethanol was demonstrated. Mice receiving daily intraperitoneal injections of MISO suffered significantly less toxicity (as determined by survival, weight gain and neurological tests) when large doses of pyridoxine-HCl (PYR) were delivered concomitantly, and consequently were able to tolerate administration of more than twice as many MISO injections. PYR did not alter the pharmacokinetics of MISO, either when given simultaneously or when given by multiple repeated daily injections prior to MISO. The administration of PYR also did not alter the radiosensitization by MISO in an in vivo-in vitro cloning assay with the EMT6 tumor in BALB/c mice. If depletion or altered metabolism of pyridoxine by reduced metabolites is also responsible for the neurotoxic effects of nitroimidazoles in humans, then concomitant administration of pyridoxine (in doses greater than the molar quantity of NH2-MISO formed) should inhibit the development of such symptoms and allow administration of larger doses of MISO than are currently clinically employable.
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D066298:In Vitro Techniques; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008920:Misonidazole / Q000378:metabolism / Q000633:toxicity*; D009374:Neoplasms, Experimental / Q000532:radiotherapy; D009420:Nervous System / Q000187:drug effects*; D009593:Nitroimidazoles / Q000633:toxicity*; D011736:Pyridoxine / Q000008:administration & dosage* / Q000378:metabolism; D012545:Schiff Bases / Q000378:metabolism; D013997:Time Factors
D009593:Nitroimidazoles; D012545:Schiff Bases; D008920:Misonidazole; D011736:Pyridoxine