Blood-brain Barrier Efflux Research Articles

Brain-to-blood efflux transport of estrone-3-sulfate at the blood-brain barrier in rats

Efflux transport of estrogens such as estrone-3-sulfate (E 1S), and estrone (E 1) across the blood-brain barrier (BBB) was evaluated using the Brain Efflux Index (BEI) method. The apparent BBB efflux rate constant (K eff) of [ 3H]E 1S, and [ 3H]E 1 was 6.63 × 10 −2 ± 0.77 × 10 −2 min −1, and 6.91 × 10 −2 ± 1.23 × 10 −2 min −1, respectively. The efflux transport of [ 3H]E 1S from brain across the BBB was a saturable process with Michaelis constant (K m) of 96.0 ± 34.4 μM and 93.4 ± 22.0 μM estimated by two different methods. By determining [ 3H]E 1S metabolites using high performance liquid chromatography (HPLC) after intracerebral injection, significant amounts of [ 3H]E 1S were found in the jugular venous plasma, providing direct evidence that most of [ 3H]E 1S is transported from brain across the BBB in intact form. To compare the apparent efflux clearance across the BBB of E 1S with that of E 1, the brain distribution volume of E 1S and E 1 was estimated using the brain slice uptake method. The apparent efflux clearance of [ 3H]E 1S was determined to be 74.9 ± 3.8 μl/(min·g brain) due to the distribution volume of 1.13 ± 0.06 ml/g brain. By contrast, the apparent efflux clearance of E 1 was more than 227 ± 3 μl/(min·g brain), since the distribution volume of [ 3H]E 1 at 60 min was 3.28 ± 0.13 ml/g. The E 1S efflux transport process was inhibited by more than 40% by coadministration of bile acids (taurocholate, and cholate), and organic anions (sulfobromophthalein, and probenecid), whereas other organic anions did not affect the E 1S efflux transport. The [ 3H]E 1S efflux was significantly reduced by 48.6% after preadministration of 5 mM dehydroepiandrosterone sulfate. These results suggest that E 1S is transported from brain to the circulating blood across the BBB via a carrier-mediated efflux transport system.