A ONE-MONTH REPEATED ORAL DOSE TOXICITY STUDY OF METHOTREXATE IN UNILATERALLY NEPHRECTOMIZED RATS

A repeated oral dose toxicity study of methotrexate(MTX)was conducted in order to examine whether the enhancement of MTX toxicity would occur in unilaterally nephrectomized(UNX)rats. UNX rats or sham-treated(SHAM)rats received dosages of 0, 0.06, 0.2 or 0.6 mg/kg/day(control animals received physiological saline). Toxic effects of MTX observed in this study were not different from studies already conducted, i.e., myelo- and lympho-toxicity, gastrointestinal toxicity, hepatotoxicity, pulmonary toxicity and renal toxicity were evident in the animals given MTX. Toxic effects of MTX in the UNX rats were more severe than those in the SHAM rats;a higher number of dead and moribund animals was observed among the UNX rats, and abnormal clinical signs appeared a few days earlier in the UNX rats. In the hematological examination, a decreased number of the blood cells in the UNX rats was observed at the lower dose level as compared to SHAM rats. The nontoxic dose of MTX in SHAM rats and UNX rats was 0.06mg/kg/day and below 0.06mg/kg/day, respectively. According to the results of a toxicokinetic examination conducted in the animals receiving 0.2mg/kg/day, AUC and T1/2terminal of MTX in the UNX rats were higher than those of SHAM rats. It was considered that the enhancement of the MTX toxicity in UNX rats was caused by the longer exposure of MTX in UNX rats. Serum UN and Cr of the UNX rats receiving physiological saline were higher than those of the corresponding SHAM rats, which suggested a slightly decreased GFR had been induced in UNX rats in this study. However, decreased PSP excretion was not observed in the UNX rats and urine volume of the UNX rats was equivalent to that of SHAM rats. Thus, it was considered that vicarious hypertrophy occurred in the residual kidney and decreased renal function was not evident in the UNX rats. This study demonstrated that the enhancement of toxicity of MTX had occurred even though a decreased renal function was not evident.