TY - JOUR
T1 - Experimental nephrotoxicity, hepatotoxicity and pharmacokinetics of cyclosporin G versus cyclosporin A
AU - Burdmann, Emmanuel A.
AU - Andoh, Takeshi F.
AU - Rosen, Seymour
AU - Lindsley, Jessie
AU - Munar, Myrna Y.
AU - Elzinga, Lawrence W.
AU - Bennett, William M.
N1 - Funding Information:
Dr. Emmanuel A. Burdmann is a recipient of a grant from "Fundacao de Amparo a Pesquisa do Estado de São Paulo" (FAPESP, São Paulo State Research Supporting Foundation), Brazil. CsA and CsG were gifts from Sandoz Research Institute, East Hanover, New Jersey, USA. This paper was presented in part at the 25th annual meeting of the American Society of Nephrology, Baltimore, Maryland, 1992 and at the XIIth International Congress of Nephrology, Jerusalem, Israel, 1993 and published in abstract form in the JAm Soc Nephrol 3:841, 1992.
PY - 1994/3
Y1 - 1994/3
N2 - 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 fibrosis 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 clearance (6.4 vs. 4.3 ml/min/kg in CsA, P < 0.0001) resulting in smaller CsG area under the curve. There was also lower renal and hepatic CsG tissue concentrations. CsA induced a dramatic decrease in GFR, 0.14 in CsA versus 0.67 ml/min/100 g in control, P < 0.001, and increased urinary excretion of N-acetyl β-D-glucosaminidase (NAG), 21 in CsA versus 13 IU/gCr in control rats, P < 0.001. CsG-treated and control rats had 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 urinary NAG (20 IU/gCr) (P < 0.01 vs. control for both). Both dosages of CsA induced considerable cortical and medullary injury (interstitial fibrosis and tubular atrophy), more severe than the histological damage found in CsG-treated rats. Neither drug promoted significant changes in liver function or histology. These results demonstrate that CsG caused less renal interstitial fibrosis and functional changes than CsA when the drugs were given at the same dosage or when similar blood levels of each drug were achieved.
AB - 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 fibrosis 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 clearance (6.4 vs. 4.3 ml/min/kg in CsA, P < 0.0001) resulting in smaller CsG area under the curve. There was also lower renal and hepatic CsG tissue concentrations. CsA induced a dramatic decrease in GFR, 0.14 in CsA versus 0.67 ml/min/100 g in control, P < 0.001, and increased urinary excretion of N-acetyl β-D-glucosaminidase (NAG), 21 in CsA versus 13 IU/gCr in control rats, P < 0.001. CsG-treated and control rats had 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 urinary NAG (20 IU/gCr) (P < 0.01 vs. control for both). Both dosages of CsA induced considerable cortical and medullary injury (interstitial fibrosis and tubular atrophy), more severe than the histological damage found in CsG-treated rats. Neither drug promoted significant changes in liver function or histology. These results demonstrate that CsG caused less renal interstitial fibrosis and functional changes than CsA when the drugs were given at the same dosage or when similar blood levels of each drug were achieved.
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U2 - 10.1038/ki.1994.92
DO - 10.1038/ki.1994.92
M3 - Article
C2 - 8196271
AN - SCOPUS:0028212794
SN - 0085-2538
VL - 45
SP - 684
EP - 691
JO - Kidney International
JF - Kidney International
IS - 3
ER -