The relationship between total kidney cyclosporin 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 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 micrograms 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 micrograms 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 In a second experiment, treatment was withdrawn after 14 days at 20 mg kg-1 day-1.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 (micrograms g-1 wet weight and micrograms 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Mead
J C
JC
Department of Medicine, University of Aberdeen, Foresterhill, UK.
Brown
P A
PA
Whiting
P H
PH
D000818:Animals; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D016572:Cyclosporine