Pharmacokinetic analysis of cyclosporine in adjuvant arthritic rats

Cyclosporine A (CsA) has been shown to be effective in patients with rheumatoid arthritis and to prevent the development and improve the symptoms of adjuvant-induced arthritis in rats. Since abnormal drug disposition has been reported in inflammatory conditions, we have evaluated the pharmacokinetics of CsA in this animal model of arthritis. We found a statistically significant decrease in the rate of disappearance of blood concentrations of CsA following iv administration to arthritic rats. The plasma half-life of CsA increased with a corresponding decrease in total body clearance. The volume of distribution remained unchanged. This abnormality in CsA kinetics was not observed in these animals until 10 days after adjuvant injection. The administration of CsA (15 mg/kg ip) twice daily to arthritic rats for 8 days produced a 39.8% and 49.5% inhibition of swelling in the right and left hindpaw, respectively. There was also a 63.5% decrease in the arthrogram score. Trough levels of CsA in arthritic animals were initially higher than in controls during this treatment but returned to control values after 8 days of dosing, suggesting reversal of abnormal disposition with improvement of the disease. The addition of indomethacin to the dosing regimen resulted in a significant increase in trough levels of CsA, indicating a drug interaction between these two compounds. Possible mechanisms responsible for these observations with CsA are discussed.