The objective of this study was to examine the concentrations in blood of cyclosporine (CyA) in rabbits during chronic subcutaneous (sc) administration and to propose a model that describes these data. Ten rabbits received sc CyA at 15 mg/kg daily for 1 week, then at 20 mg/kg twice weekly for 3 weeks, and at 15 mg/kg twice weekly for 7 weeks. Concentrations in blood were obtained weekly during the dosing period, and three to five concentrations were obtained over a 5-week period after dosing was terminated. CyA blood concentration-time (concentration in blood versus time) profiles could not be adequately described by absorption from a single dosing compartment. A two-compartment, sc absorption-site model was postulated. Steady-state concentrations in blood from three additional rabbits that had received CyA at 16.8 micrograms/min as a constant-rate intravenous infusion were added to the data set. A nonlinear mixed effects model was used to obtain the following parameter estimates (percent relative standard error): K12 = 0.111 day-1 (10.0), k21 = 0.0109 day-1 (12.6), ka = 0.0807 day-1 (11.8), CL/F = 14.6 L/day/kg (3.8), and Vd/F = 1.52 L/kg (13.4), where k12 and k21 are intercompartmental rate constants between sc compartments, ka is the absorption rate constant into the sampling compartment, CL/F is the apparent blood clearance of CyA from the body (F is bioavailability), and Vd/F is the apparent volume of distribution of CyA. The interindividual variability in CL/F was estimated as 20.5% (41.2), and the residual variability was 25.8% (15.6). The sc administration of CyA appears to provide slow, but very significant, absorption in rabbits.