Effect of bile salts on the transport of morphine-6-glucuronide in rat brain endothelial cells.

Bile salts are known to enhance the permeability of biological barriers but little is known about their effects on drug permeability across the blood-brain barrier (BBB). In this paper, the rat brain endothelial 4 (RBE4) cell monolayer incubated with astrocyte-conditioned medium was used as an in vitro model of the BBB to investigate the effects of cholate (C), 12-monoketocholate (MKC), deoxycholate (DC), and taurocholate (TC) on the transport of the hydrophilic drug, morphine-6-glucuronide (M6G). C, MKC, and TC at a concentration of 5 mM each and DC at 1 mM increased the permeability of M6G through the paracellular pathway based on a similar permeability pattern to that of sucrose. RBE4 cell uptake of M6G was unaffected by 5 mM C and TC, whereas 1 mM DC dramatically increased it due to an effect shown to be cytotoxicity as measured by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. Surprisingly, 1 mM MKC significantly increased M6G uptake without any cytotoxicity. In summary, all bile salts increased paracellular permeation of M6G but MKC also enhanced transcellular transport with little cytotoxicity. MKC appears to have the potential to modulate biophysical properties of the cell membrane or membrane-bound transporters and may therefore enhance drug delivery to the brain.