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Journal of the American Society of Nephrology, Vol 4, 168-177, Copyright © 1993 by American Society of Nephrology

REGULAR ARTICLES

Effects of cyclosporine and its metabolites in the isolated perfused rat kidney

KA Roby and LM Shaw
Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia.

The isolated perfused rat kidney (IPK) was used to study the acute effects of cyclosporin A (CsA) and its metabolites (M1, M17, M18, M21 and M-COOH). GFR, renal vascular resistance, and sodium, potassium and water reabsorption were measured before and after the addition of CsA/metabolites/vehicles. There was no difference in CsA effect (mild decrease in GFR and increase in renal vascular resistance with the inclusion of plasma (10 mL) or whole blood (20 mL) in the albumin perfusate (120 mL). Intralipid was used as the vehicle for CsA and the metabolites because methanol, ethanol, and Cremophor had significant effects on GFR. Intralipid enhanced the effect of CsA 25-fold, giving CsA dose responses comparable to those of human kidneys. This enhanced effect with intralipid was due to vasoconstriction, not vascular obstruction, and was apparently specific to CsA (no enhancement of norepinephrine with Intralipid). The primary metabolites (M1, M17, and M21) caused decreases in GFR comparable to or slightly less than those caused by CsA. The secondary metabolites (M18 and M-COOH) caused more modest declines in GFR. Cyclosporine metabolite levels in patient blood often greatly exceed levels of the parent drug; these studies suggest that the metabolites may contribute significantly to CsA nephrotoxicity in patients.




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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673