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 (E1S), 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 [H-3]E1S, and [H-3]E-1 was 6.63 x 10(-2) +/- 0.77 x 10(-2) min(-1), and 6.91 x 10(-2) +/- 1.23 x 10(-2) min(-1), respectively. The efflux transport of [H-3]E1S from brain across the BBB was a saturable process with Michaelis constant (K-m) of 96.0 +/- 34.4 muM and 93.4 +/- 22.0 muM estimated by two different methods. By determining [H-3]E1S metabolites using high performance liquid chromatography (HPLC) after intracerebral injection, significant amounts of [H-3]E1S were found in the jugular venous plasma, providing direct evidence that most of [H-3]E1S is transported from brain across the BBB in intact form. To compare the apparent efflux clearance across the BBB of E1S with that of E-1, the brain distribution volume of E1S and E-1 was estimated using the brain slice uptake method. The apparent efflux clearance of [H-3]E1S was determined to be 74.9 +/- 3.8 mul/(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 mul/(min . g brain), since the distribution volume of [H-3]E-1 at 60 min was 3.28 +/- 0.13 ml/g. The E1S 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 E1S efflux transport. The [H-3]E1S efflux was significantly reduced by 48.6% after preadministration of 5 mM dehydroepiandrosterone sulfate. These results suggest that E1S is transported from brain to the circulating blood across the BBB via a carrier-mediated efflux transport system. (C) 2000 Elsevier Science Inc. All rights reserved.