title: Experimental nephrotoxicity, hepatotoxicity and pharmacokinetics of cyclosporin G versus cyclosporin A.
abstract: 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 beta-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.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Division of Nephrology, Hypertension and Clinical Pharmacology, Oregon Health Sciences University, Portland.
authors.forename: E A
authors.initials: EA
authors.lastname: Burdmann
authors.forename: T F
authors.initials: TF
authors.lastname: Andoh
authors.forename: S
authors.initials: S
authors.lastname: Rosen
authors.forename: J
authors.initials: J
authors.lastname: Lindsley
authors.forename: M Y
authors.initials: MY
authors.lastname: Munar
authors.forename: L W
authors.initials: LW
authors.lastname: Elzinga
authors.forename: W M
authors.initials: WM
authors.lastname: Bennett
mesh_terms: D000118:Acetylglucosaminidase / Q000652:urine; D000818:Animals; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000633:toxicity*; D003524:Cyclosporins / Q000493:pharmacokinetics / Q000633:toxicity*; D004195:Disease Models, Animal; D005355:Fibrosis; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D003524:Cyclosporins; D007166:Immunosuppressive Agents; C045571:cyclosporin G; D016572:Cyclosporine; D000118:Acetylglucosaminidase