The estimation of the plasma free fraction of cyclosporine in rabbits and heart transplant patients: the application of a physiological model of renal clearance.

We estimated the free fraction (fu) of cyclosporine (CyA) in the plasma from concentrations of CyA in urine (Cu) and plasma (Cp), urine flow rate (UF), and glomerular filtration rate in rabbits and in heart transplant patients. Following intravenous administration of CyA (5-30 mg kg-1) in ten NZW rabbits and oral administration of CyA (4.8-12.1 mg kg-1) in nine heart transplant patients, CyA concentrations in urine and plasma were measured by HPLC. The ratios of Cu to Cp and UF data were fitted to a physiological model of renal clearance using NONMEM. The free fraction of cyclosporine in the rabbits and the heart transplant patients was 0.0122 and 0.14, respectively. Because of the relatively low permeability of CyA across the tubular epithelium, no apparent equilibrium between Cu and Cp at any urine flow rate was reached and, therefore, the Cu to Cp ratio will not be equal to fu.