title: Effects of the xanthine oxidase inhibitor allopurinol on the renal clearance of nitroimidazoles.
abstract: We have investigated the effects of the xanthine oxidase inhibitor allopurinol on the pharmacokinetics of nitroimidazoles in mice and dogs. Studies in mice showed that at a dose of 32 mg/kg given 30-60 min before, allopurinol had little or no effect on the clearance of misonidazole (MISO) or of the more lipophilic analogue Ro 07-0913, but did increase the blood concentrations of the hydrophilic dealkylation product desmethylmisonidazole (DEMIS). In addition, the clearances of administered DEMIS and the even more hydrophilic analogue SR-2508 were markedly reduced. This dose of allopurinol also caused a considerable fall in the clearances of 51Cr-EDTA and 125I-iodohippurate, normally used to measure glomerular filtration rate and effective renal plasma flow respectively. These data are consistent with a model in which allopurinol inhibits the renal clearance of hydrophilic nitroimidazoles. This leads to an increase in the acute toxicity of DEMIS and, to a lesser extent, of MISO. However, lower doses of allopurinol did not change the pharmacokinetics of MISO or DEMIS. A five-day pretreatment regimen (32 mg/kg/day) followed by a 66-76 hr recovery period was also without effect, thus demonstrating that the inhibition was reversible. Investigations in the dog showed that oral doses of 10-20 mg/kg allopurinol caused no change in the clearance of either 51Cr-EDTA or DEMIS.
mesh_terms: D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008920:Misonidazole / Q000031:analogs & derivatives / Q000378:metabolism; D009593:Nitroimidazoles / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
chemical_list: D009593:Nitroimidazoles; D000493:Allopurinol; D008920:Misonidazole; D014969:Xanthine Oxidase; C009997:desmethylmisonidazole