Physiologically Based Pharmacokinetics of Cyclosporine A: Extension to Tissue Distribution Kinetics in Rats and Scale-up

The tissue distribution kinetics of i.v. Cyclosporine A (CyA) was investigated extensively in rats. The concentration-to-time data of 11 organs were analyzed separately using local physiologi-cally based pharmacokinetic models, involving nonlinear plas-ma-to-blood cell distribution, membrane-permeability-limited plasma-to-tissue distribution and either linear or nonlinear tis-sue binding. Two global physiologically based pharmacokinetic models were then evaluated, each comprising arterial and ve-nous pools together with the 11 organs, adopting either of the two local models. Both global models successfully described the blood and tissue distribution kinetics of CyA. In nonlinear model, the estimated dissociation constants (Kd) for the intra-cellular saturable binding ranged 0.2 to 60 ng/ml among the organs, which are comparable with values reported for cyclo