title: Effects on enantiomeric drug disposition and open-field behavior after chronic treatment with venlafaxine in the P-glycoprotein knockout mice model.
abstract: BACKGROUND
  P-glycoprotein (P-gp) plays an important role in the efflux of drugs from the brain back into the bloodstream and can influence the pharmacokinetics and pharmacodynamics of drug molecules. To our knowledge, no studies have reported pharmacodynamic effects of any antidepressant drug in the P-gp knockout mice model.
  
  
  OBJECTIVE
  The aim of this study was to investigate the enantiomeric venlafaxine and metabolite concentrations in serum and brain of abcb1ab⁻/⁻ mice compared to wild-type mice upon chronic dosing, and to assess the effect of venlafaxine treatment on open-field behavior.
  
  
  METHODS
  P-gp knockout and wild-type mice received two daily intraperitoneal injections of venlafaxine (10 mg/kg) over ten consecutive days. Locomotor and rearing activities were assessed on days 7 and 9. After 10 days, drug and metabolite concentrations in brain and serum were determined using an enantioselective LC/MS/MS method.
  
  
  RESULTS
  The brain concentrations of venlafaxine and its three demethylated metabolites were two to four times higher in abcb1ab⁻/⁻ mice compared to abcb1ab+/+ mice. The behavioral results indicated an impact on exploration-related behaviors in the open-field as center activity was increased, and rears were decreased by venlafaxine treatment.
  
  
  CONCLUSIONS
  Our results show that P-gp at the blood-brain barrier plays an important role in limiting brain entry of the enantiomers of venlafaxine and its metabolites after chronic dosing. Taken together, the present pharmacokinetic and pharmacodynamic findings offer the possibility that the expression of P-gp in patients may be a contributing factor for limited treatment response.
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: Christoph
authors.initials: C
authors.lastname: Hiemke
authors.forename: Björn
authors.initials: B
authors.lastname: Carlsson
authors.forename: Martin
authors.initials: M
authors.lastname: Josefsson
authors.forename: Johan
authors.initials: J
authors.lastname: Ahlner
authors.forename: Finn
authors.initials: F
authors.lastname: Bengtsson
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schmitt
authors.forename: Fredrik C
authors.initials: FC
authors.lastname: Kugelberg
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency* / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D003511:Cyclohexanols / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D013237:Stereoisomerism; D013997:Time Factors; D000069470:Venlafaxine Hydrochloride
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018687:Antidepressive Agents, Second-Generation; D003511:Cyclohexanols; D000069470:Venlafaxine Hydrochloride