EXPERIMENTAL NEPHROTOXICITY, HEPATOTOXICITY AND PHARMACOKINETICS OF CYCLOSPORINE-G VERSUS CYCLOSPORINE-A

Cyclosporin G (CsG) is an analogue of cyclosporin A (CsA) with strong immunosuppressive activity. We compared these two drugs in a rat model in which salt depletion promotes irreversible renal interstitial fibr osis with renal dysfunction in animals given CsA for three weeks. When both drugs were given in the same dosage on a weight basis (15 mg/kg/ day, subcutaneously), CsA blood levels were higher than CsG (3305 vs. 1824 ng/ml, P < 0.001). This could be explained by a higher CsG cleara nce (6.4 vs. 4.3 ml/min/kg in CsA, P < 0.0001) resulting in smaller Cs G area under the curve. There was also lower renal and hepatic CsG tis sue concentrations. CsA induced a dramatic decrease in GFR, 0.14 in Cs A versus 0.67 ml/min/100 g in control, P < 0.001, and increased urinar y excretion of N-acetyl beta-D-glucosaminidase (NAG), 21 in CsA versus 13 IU/gCr in control rats, P < 0.001. CsG-treated and control rats ha d similar GFR and urinary NAG. When CsA dosage was decreased to 7.5 mg /kg blood levels were similar to those found with CsG 15 mg/kg. CsA at this dose caused a reduced GFR (0.29 ml/min/100 g) and an increased u rinary NAG (20 IU/gCr) (P < 0.01 vs, control for both). Both dosages o f CsA induced considerable cortical and medullary injury (interstitial fibrosis and tubular atrophy), more severe than the histological dama ge found in CsG-treated rats. Neither drug promoted significant change s in liver function or histology. These results demonstrate that CsG c aused less renal interstitial fibrosis and functional changes than CsA when the drugs were given at the same dosage or when similar blood le vels of each drug were achieved.