Mitamura T, Yamada A, Ishida H, Fujihira S, Ohara K, Noguchi H, Mine Y
Toxicology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
J Toxicol Sci. 1994 Nov;19(4):219-26. doi: 10.2131/jts.19.4_219.
To clarify the profile of the tacrolimus (FK506)-induced nephrotoxicity and its mechanism, 1, 2 and 4 mg/kg/day of tacrolimus was administered intramuscularly (i.m.) to spontaneous hypertensive rats (SHR) for 2 weeks, and biochemical and pathological parameters were studied in the animals. The acute nephrotoxicity of tacrolimus was characterized as increase of blood urea nitrogen (BUN) and plasma creatinine (P-Cr) levels in the groups of 1 mg/kg/day and more, decrease of creatinine clearance (CCr) value in the groups of 2 mg/kg/day and more, and histopathologically luminal narrowing of the arteriole adjacent the glomerulus in the groups of 1 mg/kg/day and more. These changes were associated with an increase of plasma renin activity (PRA) and urinary thromboxane B2 content and decrease of 6-keto-prostagrandinF1 alpha (6-keto-PGF1 alpha) content. Nilvadipine, which is one of the Ca2+ antagonist and is known to have renal vasodilating activity, prevented both biochemical and histopathological changes due to tacrolimus. The results indicated that the acute nephrotoxicity of tacrolimus was derived from impairment of glomerular function associated with the constriction of the renal arteriole brought about by the drug. All of these renal disorders induced by tacrolimus recovered completely or partially when the drug was withdrawn for 2 or 4 weeks. Consequently, the acute nephrotoxicity of tacrolimus in SHR was considered to be reversible.
为阐明他克莫司（FK506）诱导的肾毒性特征及其机制，将1、2和4mg/kg/天的他克莫司肌肉注射给自发性高血压大鼠（SHR），持续2周，并研究动物的生化和病理参数。他克莫司的急性肾毒性表现为：1mg/kg/天及以上剂量组血尿素氮（BUN）和血浆肌酐（P-Cr）水平升高；2mg/kg/天及以上剂量组肌酐清除率（CCr）值降低；组织病理学显示，1mg/kg/天及以上剂量组肾小球附近小动脉管腔狭窄。这些变化与血浆肾素活性（PRA）升高、尿血栓素B2含量增加以及6-酮-前列腺素F1α（6-keto-PGF1α）含量降低有关。尼伐地平是一种钙拮抗剂，已知具有肾血管舒张活性，可预防他克莫司引起的生化和组织病理学变化。结果表明，他克莫司的急性肾毒性源于药物引起的肾小动脉收缩相关的肾小球功能损害。当停药2或4周时，他克莫司诱导的所有这些肾脏疾病完全或部分恢复。因此，他克莫司在SHR中的急性肾毒性被认为是可逆的。
