Workman P, White R A
Biochem Pharmacol. 1982 Oct 1;31(19):3041-6. doi: 10.1016/0006-2952(82)90077-6.
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.
我们研究了黄嘌呤氧化酶抑制剂别嘌呤醇对小鼠和犬体内硝基咪唑类药物药代动力学的影响。小鼠实验表明，在给药前30 - 60分钟给予32 mg/kg的剂量时，别嘌呤醇对米索硝唑（MISO）或亲脂性更强的类似物Ro 07 - 0913的清除率几乎没有影响，但确实增加了亲水性脱烷基产物去甲基米索硝唑（DEMIS）的血药浓度。此外，所给予的DEMIS以及亲水性更强的类似物SR - 2508的清除率显著降低。该剂量的别嘌呤醇还导致通常分别用于测量肾小球滤过率和有效肾血浆流量的51Cr - EDTA和125I - 碘马尿酸盐的清除率大幅下降。这些数据与别嘌呤醇抑制亲水性硝基咪唑类药物肾清除率的模型一致。这导致DEMIS的急性毒性增加，并在较小程度上导致MISO的急性毒性增加。然而，较低剂量的别嘌呤醇并未改变MISO或DEMIS的药代动力学。为期五天的预处理方案（32 mg/kg/天），随后有66 - 76小时的恢复期，也没有产生影响，从而表明这种抑制是可逆的。犬实验表明，口服10 - 20 mg/kg的别嘌呤醇对51Cr - EDTA或DEMIS的清除率没有影响。
