title: Inhibition of P-glycoprotein enhances transport of imipramine across the blood-brain barrier: microdialysis studies in conscious freely moving rats.
abstract: OBJECTIVE
  Recent studies indicate that efflux of antidepressants by the multidrug resistance transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) may contribute to treatment-resistant depression (TRD) by limiting intracerebral antidepressant concentrations. In addition, clinical experience shows that adjunctive treatment with the P-gp inhibitor verapamil may improve the clinical outcome in TRD. Therefore, the present study aimed to investigate the effect of P-gp inhibition on the transport of the tricyclic antidepressant imipramine and its active metabolite desipramine across the BBB.
  
  
  METHODS
  Intracerebral microdialysis in rats was used to monitor brain levels of imipramine and desipramine following i.v. imipramine administration, with or without pretreatment with one of the P-gp inhibitors verapamil or cyclosporin A (CsA). Plasma drug levels were also determined at regular intervals.
  
  
  RESULTS
  Pretreatment with either verapamil or CsA resulted in significant increases in imipramine concentrations in the microdialysis samples, without altering imipramine plasma pharmacokinetics. Furthermore, pretreatment with verapamil, but not CsA, led to a significant elevation in plasma and brain levels of desipramine.
  
  
  CONCLUSIONS
  The present study demonstrated that P-gp inhibition enhanced the intracerebral concentration of imipramine , thus supporting the hypothesis that P-gp activity restricts brain levels of certain antidepressants, including imipramine. These findings may help to explain reports of a beneficial response to adjunctive therapy with verapamil in TRD.
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: F E
authors.initials: FE
authors.lastname: O'Brien
authors.forename: G
authors.initials: G
authors.lastname: Clarke
authors.forename: P
authors.initials: P
authors.lastname: Fitzgerald
authors.forename: T G
authors.initials: TG
authors.lastname: Dinan
authors.forename: B T
authors.initials: BT
authors.lastname: Griffin
authors.forename: J F
authors.initials: JF
authors.lastname: Cryan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D003891:Desipramine / Q000097:blood / Q000378:metabolism; D004347:Drug Interactions; D045604:Extracellular Fluid / Q000378:metabolism; D006207:Half-Life; D007099:Imipramine / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D017551:Microdialysis; D017397:Prefrontal Cortex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000929:Antidepressive Agents, Tricyclic; D016572:Cyclosporine; D014700:Verapamil; D007099:Imipramine; D003891:Desipramine