Pharmacokinetics and chronic toxicity of cyclosporine A in genetic hydroxylation-deficient dark Agouti rats.

Since oxidation plays a key role in the metabolism of cyclosporine A (CsA), the pharmacokinetics and the toxicity of CsA was investigated in female dark Agouti rats exhibiting a deficiency for debrisoquine hydroxylation and for dextromethorphan demethylation. When compared with Wistar rats (n = 10), dark Agouti rats (n = 10) had a higher mean clearance (4.8 ml/min per kg vs. 3.3 ml/min per kg) and a lower mean residence time (606 min vs. 1361 min) after intravenous dosing of CsA. The systemic availability of subcutaneous CsA was close to 100%. The steady state CsA concentrations assessed by HPLC in whole blood after subcutaneous dosing of 20 mg/kg per day for 23 days (n = 10) were about 1000 ng/ml in dark Agouti rats. When compared with dark Agouti rats treated with cremophore (n = 10) or not treated at all (n = 12), dark Agouti rats on chronic subcutaneous CsA plus cremophore for 23 days (n = 10) had no difference in kidney histology but had slightly increased liver fatty changes. Rats on CsA and/or cremophore had a decreased uric acid clearance and evidence of hypoaldosteronism. The urinary ratio of debrisoquine/4-hydroxydebrisoquine decreased in rats on CsA, whereas the O-demethylation and N-demethylation of liver obtained from rats on cremophore was impaired. Thus, dark Agouti rats show no difference in the metabolism of CsA and when given CsA for 23 days show drug-induced functional but no relevant structural light microscopic changes in the kidney, and functional and slight structural changes in the liver.