TIME-DEPENDENT CYCLOSPORINE-A-INDUCED NEPHROTOXICITY IN RATS

1. We investigated the toxicity of cyclosporine A (CsA) with reference to the timing of its administration in rats. 2. To elucidate the time -dependent effects of CsA on renal function and survival rate, CsA (75 mg/kg per day) or vehicle was orally administered once daily at four different times (3, 9, 15 and 21 h after lights on; HALO) over a perio d of 21 days to male Wistar rats (n = 56) kept in rooms with a 12 h li ght-dark cycle. 3. On the 7th day after treatment, creatinine clearanc es (Ccr) of groups dosed at 3 and 9 HALO (inactive period) were not re duced in comparison with clearances of time-matched control rats, wher eas Ccr significantly decreased in rats dosed at 15 and 21 HALO (activ e period). Cyclosporine A markedly increased urinary N-acetyl-beta-D-g lucosaminidase (NAG) excretion in all dosed groups at the 7th day afte r treatment, except for rats dosed at 3 HALO. In rats dosed at 3 HALO, Ccr decreased progressively; however, it did not decrease progressive ly in rats dosed at 9 HALO. In surviving rats treated during the inact ive period, urine NAG subsequently returned to control levels, Surviva l rates were greater in animals dosed during inactive periods than tho se in groups dosed during active periods. 4. Significant differences i n CsA-induced toxicity were obvious as a result of the timing of its a dministration. A different time course between Ccr and urine NAG excre tion was observed during repeated CsA administration. Degenerative cha nges in proximal tubules were demonstrated after chronic administratio n of CsA, suggesting that severe and persistent tubular damage cannot be assessed by urinary NAG excretion.