CYCLOSPORINE DISPOSITION IN THE DOG

Abstract

Radioimmunoassay (RIA) and high performance liquid chromatography (HPLC) with ultraviolet absorbance detection have been compared as potential tools for cyclosporine pharmacokinetic studies in dogs. RIA clearly affords greater assay sensitivity, although crossreactivity with cyclosporine metabolites causes an over-estimation of parent drug concentrations with a subsequent reduction in the apparent values of clearance and volume of distribution. HPLC appears to be specific for parent cyclosporine. Thus, with the sacrifice of some sensitivity, HPLC-measured time-course data afford more reliable estimates of cyclosporine pharmacokinetic parameters. After the selection of a dosage regimen from preliminary studies, the pharmacokinetics of i.v.-administered cyclosporine were studied in six adult male mongrel dogs. Following administration of 20 mg/kg by constant-rate 30-min i.v. infusion the time courses of cyclosporine were studied in plasma and urine. Concentrations were measured by reversed-phase HPLC with ultraviolet absorbance detection. Data were fitted to triexponential equations using a digital computer with the CSTRIP and NONLIN programs, and pharmacokinetic parameters were calculated. Present findings suggest that cyclosporine is slowly yet extensively distributed into peripheral body regions that might serve as slowly releasing storage areas. Large volumes of distribution along with moderately slow clearances resulted in long half-lives for the disposition of cyclosporine. Less than 1% of the administered dose was recovered as parent cyclosporine in the urine, suggesting that renal clearance of cyclosporine was negligible. The potential relevance of present findings to cyclosporine therapy of transplant patients is discussed.