Because the permeability of the blood-brain barrier to lipid microspheres (LMs) has not hitherto been demonstrated, blood-brain-barrier permeability to LM containing the prostaglandin I2 analogue clinprost has been evaluated for an in-vitro system of primary cultured monolayers of bovine brain capillary endothelial cells (BCECs), by a capillary depletion study in rats and by an in-situ brain perfusion study in normal and 4-vessel-occluded fore brain ischaemic rats. Although energy-dependency was not observed in [3H]clinprost uptake by BCECs, in accordance with results for simple diffusional transport, uptake of [3H]clinprost contained in lipid microspheres (denoted [3H]clinprost(LM)) was significantly inhibited by the endocytosis inhibitor, dansylcadaverine. The transport of LM into BCECs by endocytosis was also confirmed by fluorescence microscopy and flow-cytometric analysis using LM labelled with a fluorescent probe, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil). The absolute uptake of Dil(LM) by BCECs, measured by HPLC, was, however, almost 1/10 that of [3H]clinprost(LM), results which suggest the superiority of simple diffusion of clinprost over endocytosis of its LM form in the uptake of clinprost(LM) by BCECs. In the capillary-depletion study with rat-brain-perfused [3H]clinprost(LM) from the internal carotid artery, the parenchyma apparent distribution volume was about 45 times larger than that of the capillary, showing that [3H]clinprost(LM) was transported through the blood-brain barrier into the brain. The permeability coefficients of [3H]clinprost and [3H]clinprost(LM) determined by insitu brain perfusion in normal rats were considerably higher than those of the active metabolite [3H]isocarbacyclin and its LM form. In addition, the Blood-brain-barrier permeabilities to [3H]clinprost, [3H]isocarbacyclin and their LM forms in ischaemic rats were almost identical to those in normal rats. It was concluded that clinprost(LM) was transported through the blood-brain barrier by endocytosis of LM, simple diffusion of clinprost released from LM, and transport of isocarbacyclin generated by hydrolysis of clinprost. The blood-brain-barrier permeability of clinprost(LM) is not reduced in ischaemic conditions, because the simple diffusion of clinprost released from LM contributed mainly to clinprost(LM) transport.