甲氨蝶呤对单侧肾切除大鼠的为期一个月的重复口服剂量毒性研究。

A one-month repeated oral dose toxicity study of methotrexate in unilaterally nephrectomized rats.

作者信息

Murakami Y, Yamazaki K, Sakauchi N, Ogasawara H, Yamashita N, Masuda T, Tauchi K

机构信息

Medical Research Laboratories, Lederle (Japan), Ltd., Saitama, Japan.

出版信息

J Toxicol Sci. 1998 Nov;23 Suppl 5:681-99. doi: 10.2131/jts.23.supplementv_681.

DOI:10.2131/jts.23.supplementv_681

PMID:9891907

Abstract

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 0.06 mg/kg/day and below 0.06 mg/kg/day, respectively. According to the results of a toxicokinetic examination conducted in the animals receiving 0.2 mg/kg/day, AUC and T 1/2terminal 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.

摘要

为了研究甲氨蝶呤（MTX）毒性增强是否会在单侧肾切除（UNX）大鼠中出现，开展了一项MTX重复口服剂量毒性研究。UNX大鼠或假手术处理（SHAM）大鼠接受0、0.06、0.2或0.6 mg/kg/天的剂量（对照动物接受生理盐水）。本研究中观察到的MTX毒性作用与已开展的研究并无差异，即给予MTX的动物出现了骨髓和淋巴细胞毒性、胃肠道毒性、肝毒性、肺毒性和肾毒性。MTX对UNX大鼠的毒性作用比对SHAM大鼠更严重；UNX大鼠中观察到更多死亡和濒死动物，且UNX大鼠中异常临床体征出现时间比SHAM大鼠早几天。血液学检查中，与SHAM大鼠相比，较低剂量水平下UNX大鼠血细胞数量减少。SHAM大鼠和UNX大鼠中MTX的无毒剂量分别为0.06 mg/kg/天及低于0.06 mg/kg/天。根据对接受0.2 mg/kg/天剂量动物进行的毒代动力学检查结果，UNX大鼠中MTX的AUC和T 1/2终末值高于SHAM大鼠。认为UNX大鼠中MTX毒性增强是由于MTX在UNX大鼠体内暴露时间更长所致。接受生理盐水的UNX大鼠血清尿素氮（UN）和肌酐（Cr）高于相应的SHAM大鼠，这表明本研究中UNX大鼠的肾小球滤过率（GFR）略有降低。然而，未观察到UNX大鼠酚红排泄减少，且UNX大鼠尿量与SHAM大鼠相当。因此，认为残余肾发生了代偿性肥大，且UNX大鼠肾功能降低并不明显。本研究表明，即使肾功能降低不明显，MTX的毒性仍会增强。