title: Blood-brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein.
abstract: According to in vitro studies the enantiomers of venlafaxine display different degrees of serotonin and noradrenaline reuptake inhibition. Therefore, clarification of the enantiomeric drug distribution between serum and brain is highly warranted. To elucidate if P-glycoprotein (P-gp) in a stereoselective manner transports venlafaxine and its metabolites out of the brain we used abcb1ab double-knockout mice that do not express P-gp. A single dose of racemic venlafaxine (10 mg/kg bw) was intraperitoneally injected to knockout (-/-) and wildtype (+/+) mice. Serum and brain samples were collected 1, 3, 6 and 9 h following drug administration for analysis by LC/MS/MS. One to six hours post-dose, the brain concentrations of venlafaxine, O-desmethylvenlafaxine and N-desmethylvenlafaxine were 2-3, 2-6 and 3-12 times higher in abcb1ab (-/-) mice compared to abcb1ab (+/+) mice, respectively. No major differences in the serum and brain disposition of the S- and R-enantiomers of venlafaxine and its metabolites were found between the groups. We conclude that P-gp decreases the penetration of the S- and R-enantiomers of venlafaxine and its major metabolites into the brain. No evidence of a stereoselective P-gp mediated transport of these substances was observed.
authors.affiliation: Division of Drug Research, Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Louise
authors.initials: L
authors.lastname: Karlsson
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schmitt
authors.forename: Martin
authors.initials: M
authors.lastname: Josefsson
authors.forename: Björn
authors.initials: B
authors.lastname: Carlsson
authors.forename: Johan
authors.initials: J
authors.lastname: Ahlner
authors.forename: Finn
authors.initials: F
authors.lastname: Bengtsson
authors.forename: Fredrik C
authors.initials: FC
authors.lastname: Kugelberg
authors.forename: Christoph
authors.initials: C
authors.lastname: Hiemke
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D003511:Cyclohexanols / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D013237:Stereoisomerism; D000069470:Venlafaxine Hydrochloride
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003511:Cyclohexanols; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride