AbstractWe 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 ofCutoCpand 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 betweenCuandCpat any urine flow rate was reached and, therefore, theCutoCpratio will not be equ