Accelerated elimination of pimonidazole following microsomal enzyme induction in mice: a possible approach to reduced neurotoxicity of the pimonidazole-etanidazole combination.
The pimonidazole-etanidazole combination shows promise for improved radiosensitization, although pimonidazole may increase the dose-limiting peripheral neurotoxicity of etanidazole in man. Induction of liver microsomal drug metabolizing enzymes by phenobarbitone resulted in reduced exposure to pimonidazole in plasma, brain, and tumor in mice. Peak tumor concentrations were lowered, but to a lesser extent. Phenobarbitone induction caused no change in the urinary ratio of pimonidazole to its N-oxide metabolite, and in fact, markedly reduced the circulating metabolite concentrations in plasma. There was no effect of phenobarbitone on plasma or tissue pharmacokinetics of etanidazole, which is eliminated by renal clearance. The results suggest that hepatic microsomal enzyme induction may be a possible approach to reducing the toxicity of the pimonidazole-etanidazole combination, and may also provide valuable information on the enzymology of pimonidazole metabolism.
Workman
P
P
MRC Clinical Oncology and Radiotherapeutics Unit, MRC Centre, Cambridge, UK.
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004338:Drug Combinations; D004790:Enzyme Induction; D017341:Etanidazole; D051379:Mice; D008809:Mice, Inbred C3H; D008862:Microsomes, Liver / Q000201:enzymology*; D009368:Neoplasm Transplantation; D009593:Nitroimidazoles / Q000493:pharmacokinetics* / Q000633:toxicity; D010634:Phenobarbital; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D012513:Sarcoma, Experimental / Q000378:metabolism
D004338:Drug Combinations; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D017341:Etanidazole; C033815:pimonidazole; D010634:Phenobarbital