title: Effects of sertraline and fluoxetine on p-glycoprotein at barrier sites: in vivo and in vitro approaches.
abstract: OBJECTIVE
  Retention of substances from systemic circulation in the brain and testes are limited due to high levels of P-glycoprotein (P-gp) in the luminal membranes of brain and testes capillary endothelial cells. From a clinical perspective, P-gp rapidly extrudes lipophilic therapeutic agents, which then fail to reach efficacious levels. Recent studies have demonstrated that acute administration of selective serotonin reuptake inhibitors (SSRI) can affect P-gp function, in vitro and in vivo. However, little is known concerning the time-course of these effects or the effects of different SSRI in vivo.
  
  
  METHODS
  The P-gp substrate, tritiated digoxin ([(3)H] digoxin), was co-administered with fluoxetine or sertraline to determine if either compound increased drug accumulation within the brains and testes of mice due to inhibition of P-gp activity. We undertook parallel studies in endothelial cells derived from brain microvessels to determine the dose-response and time-course of effects.
  
  
  RESULTS
  In vitro, sertraline resulted in rapid and potent inhibition of P-gp function in brain endothelial cells, as determined by cellular calcein accumulation. In vivo, a biphasic effect was demonstrated. Brain accumulation of [(3)H] digoxin was increased 5 minutes after treatment with sertraline, but by 60 minutes after sertraline treatment, brain accumulation of digoxin was reduced compared to control. By 240 minutes after sertraline treatment brain digoxin accumulation was elevated compared to control. A similar pattern of results was obtained in the testes. There was no significant effect of fluoxetine on P-gp function, in vitro or in vivo.
  
  
  CONCLUSIONS
  Acute sertraline administration can modulate P-gp activity in the blood-brain barrier and blood-testes barrier. This clearly has implications for the ability of therapeutic agents that are P-gp substrates, to enter the brain when co-administered with SSRI.
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA. akapoor@wisc.edu
authors.forename: Amita
authors.initials: A
authors.lastname: Kapoor
authors.forename: Majid
authors.initials: M
authors.lastname: Iqbal
authors.forename: Sophie
authors.initials: S
authors.lastname: Petropoulos
authors.forename: Hay Lam
authors.initials: HL
authors.lastname: Ho
authors.forename: William
authors.initials: W
authors.lastname: Gibb
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Matthews
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism*; D001814:Blood-Testis Barrier / Q000187:drug effects* / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology*; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005473:Fluoxetine; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline