The purpose of this study was to investigate the impact of different lipid based formulations of lipophilic drugs on in vitro solubilization and intestinal ex vivo permeability processes. Thereafter, to evaluate the ability of these in vitro and ex vivo results to predict the corresponding in vivo oral bioavailability data. The dissolution of dexamethasone and griseofulvin in long (LCT), medium (MCT) and short (SCT) chain triglyceride formulations was tested in a dynamic in vitro lipolysis model. Following the completion of the lipolysis, the permeability through the gut wall was tested in an ex vivo side-by-side diffusion chamber model. The absolute oral bioavailability of the drugs from the tested formulations was investigated in rats. The dynamic in vitro lipolysis experiments indicated an equivalent performance of the different formulations for dexamethasone, and a performance rank order of MCT>LCT>SCT>H(2)O for griseofulvin. In the subsequent ex vivo permeability studies, the SCT formulation caused enhanced permeation with doubled permeability coefficient for both drugs. The in vivo bioavailability of both drugs correlated well with the in vitro data, i.e., LCT=MCT=SCT for dexamethasone and MCT>LCT>SCT>H(2)O for griseofulvin, despite the significant augmented intestinal permeability produced by the SCT formulation. In conclusion, the in vitro lipolysis model was found to be useful in the intelligent optimization of oral lipid formulations for lipophilic drugs, even in the case where the intestinal permeability is enhanced by the formulation. The SCT vehicle showed to be a potential permeability enhancer; however, for class 2 compounds, the permeability does not correlate with in vivo bioavailability.