Ciclosporinの腎毒性に関する研究 第2報: CiclosporinおよびSulfamethoxazole-Trimethoprim合剤併用投与によるラットの腎毒性について

Abstract

Ciclosporinおよびsulfamethoxazole-trimethoprim合剤の併用投与による腎毒性について, ラットを用いて生化学的, 形態学的に検討した.腎毒性による腎機能障害はBUNの上昇, 血清クレアチニンの上昇, それにクレアチニン・クリアランス低下としてあらわれたが, 尿中のN-acetyl-β-D-glucosaminidase活性の有意な変動はなかった.併用投与群の腎障害はciclosporin単独投与群に比べ増強される傾向があった.ciclosporinの血清濃度は併用投与時には単独投与時より低下する傾向がみられ, sulfamethoxazoleとtrimethoprimの血清濃度は併用投与時ciclosporinの投与量が増えると高くなる傾向があった.腎の組織所見は, 病変の主体は尿細管にみられ, 近位尿細管上皮細胞の空胞変性とlysosomeの増加をみたが, dose-relatedな傾向はなかった

A cyclosporin (CS) has a serious nephrotoxic effect which is synergistic with sulfamethoxazole-trimethoprim (ST) on renal allograft recipients. The effects of CS and ST on renal function and structure, were examined biochemically and morphologically in rats. Male Wistar rats each weighing 250 g were given various dose regimens (CS 50 mg/kg + ST 600 mg/kg, CS 25 mg/kg + ST 600 mg/kg, CS 10 mg/kg + ST 600 mg/kg) orally for 21 days, and were killed and examined on the 22nd day. Blood urea nitrogen (BUN), serum and urinary creatinine, and urinary N-acetyl-s-D-glucosaminidase (NAG) were measured before administration and on the 7th, 14th and 21st day after administration. The serum levels of CS, sulfamethoxazole (SMX) and trimethoprim (TMP) were measured on the 21st day after administration. Kidneys were examined by light and electron microscopy. All rats that had received 50 mg/kg CS and 600 mg/kg ST died within 9 days after a severe loss in body weight. Rats that had received 25 mg/kg CS and 600 mg/kg ST had lost weight. A high dose CS and ST caused a significant elevation of BUN. The level of serum creatinine was significantly elevated only in rats that had received 25 mg/kg CS and 600 mg/kg ST. Decrease in creatinine clearance was not significant and the urinary NAG activity was not altered significantly during the experimental course. Morphological alterations were confined to the proximal tubuli and they consisted of PAS positive globules, loss of nuclei, tubular cell vacuolation and increased number of lysosomes. However, these alterations were mild and not related to the dose of CS and ST.(ABSTRACT TRUNCATED AT 250 WORDS)