title: Mechanistic studies of the effect of bile salts on rhodamine 123 uptake into RBE4 cells.
abstract: To examine the ability of bile salts (BS) to act as permeation enhancers at the blood brain barrier, the effect of four BS (cholate, deoxycholate, monoketocholate and taurocholate) on accumulation of rhodamine 123 (R123) in rat brain endothelial (RBE4) cells was investigated. Experiments were performed using BS concentrations shown to be noncytotoxic to RBE4 cells. Uptake and efflux of R123 in the absence and presence of BS were studied by fluorescence spectroscopy and confocal microscopy. Changes in RBE4 cell membrane fluidity in the presence of BS were evaluated using fluorescence anisotropy. The direct interaction between BS and R123 (ion pairing) and the effect of BS on distribution of R123 into liposomes were studied by capillary electrophoresis. All BS influenced R123 uptake in a concentration-dependent manner and increased cell membrane fluidity. Monoketocholate produced the greatest increase in uptake and also significantly reduced R123 efflux probably by inhibition of P-glycoprotein (P-gp). Direct interaction of BS and R123 was weak, but distribution of R123 into liposomes was increased by BS. The results suggest that BS increase R123 uptake by increasing cell membrane fluidity and, in the case of MKC, by inhibiting P-gp.
authors: School of Pharmacy, University of Otago, Dunedin, New Zealand. lin.yang@otago.ac.nz
authors: Lin
authors: L
authors: Yang
authors: J Paul
authors: JP
authors: Fawcett
authors: Jesper
authors: J
authors: Østergaard
authors: Hu
authors: H
authors: Zhang
authors: Ian G
authors: IG
authors: Tucker
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors; D000818:Animals; D001647:Bile Acids and Salts / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D002635:Chenodeoxycholic Acid / Q000009:adverse effects / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D004339:Drug Compounding; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008081:Liposomes; D008560:Membrane Fluidity / Q000187:drug effects; D049990:Membrane Transport Modulators / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D008954:Models, Biological; D009994:Osmolar Concentration; D014677:Pharmaceutical Vehicles / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D020112:Rhodamine 123 / Q000737:chemistry / Q000378:metabolism*; D013499:Surface Properties
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D001647:Bile Acids and Salts; D005456:Fluorescent Dyes; D008081:Liposomes; D049990:Membrane Transport Modulators; D014677:Pharmaceutical Vehicles; D002635:Chenodeoxycholic Acid; D020112:Rhodamine 123; C025576:3,7-dihydroxy-12-oxocholanoic acid