title: The role of P-glycoprotein in CNS antihistamine effects.
abstract: BACKGROUND
  P-glycoprotein (P-gp) is a drug efflux pump expressed, amongst others, on the luminal surface of the cerebral endothelial cells forming the blood-brain barrier. Studies in rodents have demonstrated that antihistamines that are substrates of the P-gp transporter display no or minor central nervous system (CNS) effects as compared to antihistamines that are not P-gp transporter substrates.
  
  
  OBJECTIVE
  The present study explored whether P-gp contributes in similar ways to the occurrence of sedative effects of antihistamines in humans.
  
  
  METHODS
  An fMRI study was conducted according to a double-blind, randomized, placebo-controlled, cross-over design in 13 healthy volunteers. Participants received cetirizine 15 mg (an antihistamine), verapamil 120 mg (a P-gp blocker), a combination of cetirizine + verapamil, and a placebo. Brain activity was assessed while conducting the attention network test (ANT) in a 3T magnetic resonance scanner. The ANT measures three independent attention domains: i.e., alerting, orienting, and executive attention. It was expected that the combined treatment of cetirizine with verapamil would prevent efflux of cetirizine from the CNS, thus increasing attentional impairment, as compared to cetirizine administered alone.
  
  
  RESULTS
  The present study provides evidence that the P-gp transporter is involved in central antihistamine effects in humans. Participants were less alert during the combined treatment of cetirizine and verapamil as indicated by longer reaction times and decreased blood oxygen level-dependent response in the right superior temporal gyrus.
  
  
  CONCLUSIONS
  It is concluded that the affinity for the P-gp transporter may contribute to the lower incidence of CNS side effects of certain antihistamines.
authors.affiliation: Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands. silke.conen@manchester.ac.uk
authors.forename: Silke
authors.initials: S
authors.lastname: Conen
authors.forename: Eef L
authors.initials: EL
authors.lastname: Theunissen
authors.forename: Annemiek
authors.initials: A
authors.lastname: Vermeeren
authors.forename: Peter
authors.initials: P
authors.lastname: van Ruitenbeek
authors.forename: Peter
authors.initials: P
authors.lastname: Stiers
authors.forename: Mitul A
authors.initials: MA
authors.lastname: Mehta
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Toennes
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Ramaekers
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000328:Adult; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D017332:Cetirizine / Q000008:administration & dosage*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D039563:Histamine H1 Antagonists, Non-Sedating / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D014700:Verapamil / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D039563:Histamine H1 Antagonists, Non-Sedating; D014700:Verapamil; D017332:Cetirizine
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