Active efflux of the 5-HT1A receptor agonist flesinoxan via P-glycoproteinat the blood-brain barrier

The role of P-glycoprotein on the efflux of the 5-HT1A receptor agonist fle sinoxan across the blood-brain barrier in vivo and in vitro was investigate d. In vitro. the transport ratios (representing polarized transport) of fle sinoxan ( 10 mug/ml) were 4.2 in the MDR1-transfected LLC-PK1 cell line. wh ich could be inhibited by the Pgp modulators SDZ-PSC 833 and LY 335979 and 1.1 in the wild-type LLC-PK1 cell line after 4 h. Flesinoxan concentrations lower than 33 mug/ml were actively transported by Pgp, while at higher con centrations Pgp became saturated and transport in the MDR1-transfected cell line was comparable with the wild-type cell line, In the in vitro BBB co-c ulture model the transport ratio was 2.0 and was decreased to 1.0 in the pr esence of Pgp modulators. In vivo, the accumulation of flesinoxan in the br ain at 3 It was much higher in the mdr1a(-/-) mice compared to mdr1a(+/+) m ice (ratio 12.6 and 27.0 at dose levels of 3 mg/kg and 10 mg/kg respectivel y). In conclusion. both in vivo as well as in vitro results have demonstrat ed that Pgp is a limiting factor for the transport of the 5-HT1A receptor a gonist flesinoxan into the CNS. This should be considered when its applicat ion in therapy is combined with other Pgp substrates. (C) 2001 Elsevier Sci ence BY. All rights reserved.