The effect of vitamin B6 on the neurotoxicity and pharmacology of desmethylmisonidazole and misonidazole: clinical and laboratory studies.
The clinical usefulness of misonidazole (MISO) and desmethylmisonidazole (DMM) is severely limited by neurotoxicity. Based on theoretical considerations and on laboratory data suggesting that pyridoxine (PN) decreased MISO toxicity in mice, we attempted to ameliorate the clinical neuropathy of DMM using oral PN. Pharmacokinetic analysis suggested interaction of PN and DMM but no protection against neuropathy was observed. Serial experiments with C3H and BALB/c mice were done using various forms of vitamin B6 (PN, pyridoxal, pyridoxal phosphate) administered orally and i.p. and the nonspecific adsorbing agent activated charcoal. No consistent protection was observed. A slower rate of drug delivery (dose/day) allowed a larger cumulative dose of MISO to be given, a result paradoxical to that seen in the clinic. Dexamethasone did not alter MISO toxicity in mice, contrary to the clinical findings. We conclude that vitamin B6 is not useful in preventing clinical neurotoxicity of MISO or DMM. Furthermore, this mouse model of neurotoxicity assessment has produced results inconsistent with those seen clinically.
D000818:Animals; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008920:Misonidazole / Q000031:analogs & derivatives / Q000378:metabolism / Q000506:poisoning*; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000517:prevention & control; D009593:Nitroimidazoles / Q000506:poisoning*; D011736:Pyridoxine / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000378:metabolism / Q000506:poisoning*
D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D008920:Misonidazole; C009997:desmethylmisonidazole; D011736:Pyridoxine