Effects of the xanthine oxidase inhibitor allopurinol on the renal clearance of nitroimidazoles.
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.
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*
D009593:Nitroimidazoles; D000493:Allopurinol; D008920:Misonidazole; D014969:Xanthine Oxidase; C009997:desmethylmisonidazole