The specific aims of this research application are to characterize the pharmacokinetic disposition of Cyclosporine (CSP) and its major metabolites in patients undergoing bone marrow transplantation for aplastic anemia or hematologic malignancy. We plan to use a specific high-pressure liquid chromatographic procedure developed in our laboratory to quantitate CSP. Serial blood and urine samples will be collected to obtain a pharmacokinetic profile for SCP and its major metabolites following oral and intravenous administration. Concentration versus time data will be fitted by computer to the appropriate pharmacokinetic mammilary model. Half-lives, systemic and renal clearance, volume of distribution, and absorption rate constant will be calculated with standard pharmacokinetic equations. Cyclosporine concentrations after oral administration will be compared to those after intravenous administration to calculate the absolute bioavailability of the oral solution. Cyclosporine and CSP metabolite concentrations will be correlated with concurrently collected clinical data to determine the effects of hepatic and renal dysfunction, oral nonabsorbable antibiotics, and acute graft-versus-host disease on CSP or CSP metabolite pharmacokinetics. The results of this study may aid in the design of rational CSP dosing regimens, defining optimal serum CSP concentrations, and adjusting CSP dosage in the presence of organ dysfunction or other clinical features.
