title: Active efflux of the 5-HT(1A) receptor agonist flesinoxan via P-glycoprotein at the blood-brain barrier.
abstract: The role of P-glycoprotein on the efflux of the 5-HT(1A) receptor agonist flesinoxan across the blood-brain barrier in vivo and in vitro was investigated. In vitro, the transport ratios (representing polarized transport) of flesinoxan (10 microg/ml) were 4.2 in the MDR1-transfected LLC-PK1 cell line, which 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 microg/ml were actively transported by Pgp, while at higher concentrations 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-culture model the transport ratio was 2.0 and was decreased to 1.0 in the presence of Pgp modulators. In vivo, the accumulation of flesinoxan in the brain at 3 h was much higher in the mdr1a(-/-) mice compared to mdr1a(+/+) mice (ratio 12.6 and 27.0 at dose levels of 3 mg/kg and 10 mg/kg respectively). In conclusion, both in vivo as well as in vitro results have demonstrated that Pgp is a limiting factor for the transport of the 5-HT(1A) receptor agonist flesinoxan into the CNS. This should be considered when its application in therapy is combined with other Pgp substrates.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, P.O. Box 9503, 2300 RA, Leiden, The Netherlands.
authors.forename: I C
authors.initials: IC
authors.lastname: van der Sandt
authors.forename: R
authors.initials: R
authors.lastname: Smolders
authors.forename: L
authors.initials: L
authors.lastname: Nabulsi
authors.forename: K P
authors.initials: KP
authors.lastname: Zuideveld
authors.forename: A G
authors.initials: AG
authors.lastname: de Boer
authors.forename: D D
authors.initials: DD
authors.lastname: Breimer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active; D001812:Blood-Brain Barrier / Q000502:physiology*; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D019450:Genes, MDR / Q000235:genetics; D018374:LLC-PK1 Cells; D051379:Mice; D008815:Mice, Inbred Strains; D010879:Piperazines / Q000493:pharmacokinetics*; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics*; D013552:Swine; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010879:Piperazines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; C056895:flesinoxan