PHARMACOKINETICS OF CYCLOSPORINE AND STEADY-STATE ASPIRIN DURING COADMINISTRATION

Anecdotal reports from clinical trials assessing the use of cyclospori ne in the treatment of rheumatoid arthritis suggest an association bet ween enhanced renal impairment ad combined use of cyclosporine with no nsteroidal anti-inflammatory drugs. To explore possible pharmacokineti c contributions to this phenomenon, a randomized, two-period crossover investigation was performed in 24 healthy volunteers in which a singl e oral dose of 300 mg cyclosporine was administered alone and on day 1 0 of multiple oral dosing of aspirin 960 mg three times daily. Serial blood samples were obtained over 48 hours after each cyclosporine dose and over a steady-state dosing interval for aspirin on day 9 (aspirin alone) and day 10 (coadministration of cyclosporine and aspirin). Cyc losporine whole blood concentrations were determined by a specific mon oclonal radioimmunoassay and plasma concentrations of acetylsalicylic acid and metabolites by high-performance liquid chromatography. Lack o f a pharmacokinetic interaction was conclusively demonstrated for the rate and extent of cyclosporine and acetylsalicylic acid absorption an d.for the rate and extent of salicylic acid formation after a single d ose of cyclosporine was coadministered during steady-state aspirin dos ing. If a clear association between enhanced renal impairment and the combined use of cyclosporine and aspirin is substantiated, the underly ing mechanism appears to be pharmacodynamic rather than pharmacokineti c.