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The Relationship Between Total Kidney Cyclosporin A Concentrations, Trough Drug Levels and Renal Function in the Rat Following Withdrawal of Treatment

Department of Medicine and Therapeutics, University of Aberdeen, Medical Buildings, Foresterhill, Aberdeen AB9 2ZD, UK, Department of Clinical Biochemistry, University of Aberdeen, Medical Buildings, Foresterhill, Aberdeen AB9 2ZD, UK

P.A.J. Brown

Department of Pathology, University of Aberdeen, Medical Buildings, Foresterhill, Aberdeen AB9 2ZD, UK

P.H. Whiting

Department of Clinical Biochemistry, University of Aberdeen, Medical Buildings, Foresterhill, Aberdeen AB9 2ZD, UK

Groups of 6 male rats received cyclosporin A (CsA: 20 mg kg^-1 day^-1) by gavage for either 4, 7, 10 or 14 days and were sacrificed 24 hours later. CsA nephrotoxicity was characterised functionally by decreased creatinine clearance rates and increased enzymuria. A significant correlation (r2=0.980; P<0.01 ) was observed between the CsA concentration in renal tissue (4.88± 2.16, 13.54± 3.68, 25.71±6.59 and 36.64± 6.797 µg g^-1 kidney wet weight, [mean±SD] on days 4, 7, 10 and 14 respectively) and trough whole blood (TWB) CsA concentrations (0.86± 0.18, 1.82± 0.59, 3.35± 0.52 and 3.70± 1.12 µg ml^-1, respectively) was observed. Furthermore, an apparent relationship between both renal tissue and TWB CsA concentration, the degree of renal microcalcification (MC) at the cortico-medullary junction and magnitude of the renal dysfunction was observed. In a second experiment, treatment was withdrawn after 14 days at 20 mg kg^-1 day^-1. Following withdrawal of treatment for 1, 4, 7, 10 or 14 days, renal tissue and whole blood CsA concentrations fell progressively from 32.23± 11.23 and 3.01±0.96 (µg g^-1 wet weight and µg ml^-1, respectively) to 25.66±9.77 and 2.12± 0.66, 10.42± 0.65 and 0.78± 0.23, 4.35± 1.2 and 0.51± 0.16, 3.98± 3.76 and 0.27± 0.03, and 2.58± 1.56 and Not Detected. However, the severity of MC was maintained over this period and while values for urinary flow rate, glycosuria and NAG were similar to pretreatment values by day 14, those for creatinine clearance rate were not (325± 43 v 421 ± 91 ml h^-1 kg^-1 body weight [mean±SD], P<0.01). These results suggest that MC, an early feature of chronic CsA toxicity is both irreversible and not related to either TWB or tissue CsA concentrations.

Human & Experimental Toxicology, Vol. 13, No. 7, 506-511 (1994)
DOI: 10.1177/096032719401300710


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