THE RELATIONSHIP BETWEEN TOTAL KIDNEY CYCLOSPORINE-A CONCENTRATIONS, TROUGH DRUG LEVELS AND RENAL-FUNCTION IN THE RAT FOLLOWING WITHDRAWAL OF TREATMENT

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 hou rs later. CsA nephrotoxiciiy was characterised functionally by decreas ed creatinine clearance rates and increased enzymuria, A significant c orrelation (r(2)=0.980; P<0.01) was observed between the CsA concentra tion in renal tissue (4.88+/-2.16, 13.54+/-3.68, 25.71+/-6.59 and 36.6 4+/-6.797 mu g g(-1) kidney wet weight, [mean+/-SD] on days 4, 7, 10 a nd 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 mu g ml(-1), resp ectively) was observed, Furthermore, an apparent relationship between both renal tissue and TWB CsA concentration, the degree of renal micro calcification (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 In a second experiment, treatment was withdrawn after 14 days at 20 mg kg(-1) day(-1), Following withdra wal of treatment for 1, 4, 7, 10 or 14 days, renal tissue and whole bl ood CsA concentrations fell progressively from 32.23+/-11.23 and 3.01/-0.96 (mu g g(-1) wet weight and mu g 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 Detec ted. However, the severity of MC was maintained over this period and w hile values for urinary flow rate, glycosuria and NAG were similar to pretreatment values by day 14, those for creatinine clearance rate wer e 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,