1999 Volume 14 Issue supplement Pages 108-109
In this study, we focused on the transport characteristics of tolbutamide and glibenclamide to investigate transport mechanism from blood to brain and/or from brain to blood across Blood-Brain Barrier by using in vitro experiments. We examined the transport of [14C]tolbutamide and [3H]glibenclamide in Pgp (mdrla, mdrlb, MDR1)-expressing cell lines and a MRP1-expressing cell line to investigate the efflux mechanisms of these drugs. We found that Pgp transports glibenclamide but not tolbutamide, and contributes to the low brain distrubution of glibenclamide, whereas a different efflux mechanism is involved in the case of tolbutamide. We also investigated the uptake of tolbutamide from the blood site into brain endothelial cells using MBEC4 cell line. The uptake of [14C]tolbutamide by MBEC4 cells is saturable, dependent on temperature and energy. The uptake coefficient increased markedly with decreasing pH of the external medium from neutral to acidic. Replacement of chloride with sulfate or gluconate significantly increased the initial uptake of [14C]tolbutamide, while replacement with nitrate significantry decreased it. Moreover, the upteke was significantly increased by valinomycin and reduced by an anion-exchange inhibitor, DIDS. The initial uptake of [14C]tolbutamide was significantly reduced by several sulfa drugs, probenecid, sulfinpylazone, salicylic acid and valproic acid. These results indicate the existence of a pH and membrane-potential-dependent anion exchange system for concentrative uptake of tolbutamide and various organic anions in MBEC4 cells. These findings suggested that BBB transport of organic anions such as tolbutamide is regulated by two transport systems which are influx and efflux transport systems.
