Pharmacokinetic changes of methotrexate after intravenous administration to uranyl nitrate-induced acute renal failure rats.

Abstract

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.