Park J M, Moon C H, Lee M G
College of Medicine, Ajou University, Suwon, Korea.
Res Commun Mol Pathol Pharmacol. 1996 Sep;93(3):353-62.
The pharmacokinetic changes of methotrexate (MTX) were investigated after 1-min intravenous (iv) administration of MTX, 8 mg/kg, to the control and the uranyl nitrate-induced acute renal failure (U-ARF) rats. The impaired kidney and liver functions were observed by pretreatment with urinary nitrate based on physiological parameters of plasma and urine, and the tissue microscopy. After 1-min iv infusion of MTX, the plasma concentrations of MTX (except at 1 min) and the total area under the plasma concentration-time curves of MTX (542 versus 297 micrograms min/ml) increased significantly in the U-ARF rats when compared to those in the control rats. This was due to the significantly slower in total body clearance (CL) of MTX (15.2 versus 27.5 ml/min/kg) in the U-ARF rats than that in the control rats. The significantly slower in CL of MTX in the U-ARF rats was due to the significantly slower both renal (1.01 versus 8.39 ml/min/kg, because of the considerably decreased renal tubular secretion of MTX) and nonrenal (14.2 versus 19.1 ml/min/kg, because of the considerably decreased liver metabolism) clearances in the U-ARF rats. All 11 control rats survived until sacrificed (24 h), however, 5 out of 15 U-ARF rats died within 7 h after iv administration of MTX. If the present rat data were to be extrapolated to human beings, iv dose of MTX need to be modified in the acute renal failure patients.
对对照组大鼠和硝酸铀酰诱导的急性肾衰竭（U-ARF）大鼠静脉注射（iv）8mg/kg甲氨蝶呤（MTX）1分钟后，研究了MTX的药代动力学变化。基于血浆和尿液的生理参数以及组织显微镜检查，通过用硝酸铀预处理观察肾功能和肝功能受损情况。静脉输注MTX 1分钟后，与对照组大鼠相比，U-ARF大鼠的MTX血浆浓度（1分钟时除外）和MTX血浆浓度-时间曲线下的总面积（542对297微克·分钟/毫升）显著增加。这是由于U-ARF大鼠中MTX的全身清除率（CL）（15.2对27.5毫升/分钟/千克）明显低于对照组大鼠。U-ARF大鼠中MTX的CL明显减慢是由于U-ARF大鼠的肾清除率（1.01对8.39毫升/分钟/千克，因为MTX的肾小管分泌显著减少）和非肾清除率（14.2对19.1毫升/分钟/千克，因为肝脏代谢显著减少）均明显减慢。所有11只对照大鼠均存活至处死（24小时），然而，15只U-ARF大鼠中有5只在静脉注射MTX后7小时内死亡。如果将目前大鼠的数据外推至人类，急性肾衰竭患者的MTX静脉注射剂量需要调整。
