Since cyclosporine is heavily bound to plasma lipoproteins, its pharmacokinetic profile was evaluated in the Zucker hyperlipidemic rat model (N = 4) and compared to Zucker lean (N = 4) and Sprague-Dawley (N = 4) rat models. Following a single i.v. dose (5 mg/kg) of cyclosporine, serial blood samples, collected by tail bleed, were assayed for cyclosporine concentration by radioimmunoassay. Pharmacokinetic analysis was performed by standard non-compartmental methods. Half-lives between the three groups were not different. However, Zucker obese rats demonstrated a significantly smaller volume of distribution at steady-state (2.8 +/- 1.1 L/kg; p less than 0.01) versus the Zucker lean (5.4 +/- .9 L/kg) and Sprague-Dawley rats (5.6 +/- .7 L/kg). Likewise, the total body clearance was markedly reduced in the obese (0.24 +/- .09 L/h/kg; p less than 0.01) versus lean (0.51 +/- .04 L/h/kg) and Sprague-Dawley (0.52 +/- .06 L/h/kg) rat models. This data suggests the ability of lipids to significantly impair the intracellular transfer of cyclosporine and may impact on its clinical monitoring, efficacy and toxicity.