title: Blood-brain-barrier transport of lipid microspheres containing clinprost, a prostaglandin I2 analogue.
abstract: 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.
authors.affiliation: Research Center, Taisho Pharmaceutical Co. Ltd, Saitama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Minagawa
authors.forename: K
authors.initials: K
authors.lastname: Sakanaka
authors.forename: S
authors.initials: S
authors.lastname: Inaba
authors.forename: Y
authors.initials: Y
authors.lastname: Sai
authors.forename: I
authors.initials: I
authors.lastname: Tamai
authors.forename: T
authors.initials: T
authors.lastname: Suwa
authors.forename: A
authors.initials: A
authors.lastname: Tsuji
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D002545:Brain Ischemia / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D004337:Drug Carriers; D011464:Epoprostenol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008055:Lipids; D008863:Microspheres; D010539:Permeability; D011465:Prostaglandins, Synthetic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D004337:Drug Carriers; D008055:Lipids; D011465:Prostaglandins, Synthetic; C052840:TEI 9090; C041946:9-O-methanoprostaglandin I; D011464:Epoprostenol