title: Brain histamine H receptor occupancy of orally administered antihistamines measured by positron emission tomography with (11)C-doxepin in a placebo-controlled crossover study design in healthy subjects: a comparison of olopatadine and ketotifen.
abstract: OBJECTIVE
  The strength of sedation due to antihistamines can be evaluated by using positron emission tomography (PET). The purpose of the present study is to measure histamine H(1) receptor (H(1)R) occupancy due to olopatadine, a new second-generation antihistamine and to compare it with that of ketotifen.
  
  
  METHODS
  Eight healthy males (mean age 23.5 years-old) were studied following single oral administration of olopatadine 5 mg or ketotifen 1 mg using PET with (11)C-doxepin in a placebo-controlled crossover study design. Binding potential ratio and H(1)R occupancy were calculated and were compared between olopatadine and ketotifen in the medial prefrontal (MPFC), dorsolateral prefrontal (DLPFC), anterior cingulate (ACC), insular (IC), temporal (TC), parietal (PC), occipital cortices (OC). Plasma drug concentration was measured, and correlation of AUC to H(1)R occupancy was examined.
  
  
  RESULTS
  H(1)R occupancy after olopatadine treatment was significantly lower than that after ketotifen treatment in the all cortical regions (P < 0.001). Mean H(1)R occupancies for olopatadine and ketotifen were, respectively: MPFC, 16.7 vs. 77.7; DLPFC, 14.1 vs. 85.9; ACC, 14.7 vs. 76.1; IC, 12.8 vs. 69.7; TC, 12.5 vs. 66.5; PC, 13.9 vs. 65.8; and OC, 19.5 vs. 60.6. Overall cortical mean H(1)R occupancy of olopatadine and ketotifen were 15% and 72%, respectively. H(1)R occupancy of both drugs correlated well with their respective drug plasma concentrations (P < 0.001).
  
  
  CONCLUSIONS
  It is suggested that 5 mg oral olopatadine, with its low H(1)R occupancy and thus minimal sedation, could safely be used an antiallergic treatment for various allergic disorders. Abbreviations histamine H(1) receptor (H(1)R), histamine H(1) receptor occupancy (H(1)RO), dopamine D(2) receptor (D(2)R), positron emission tomography (PET), blood-brain barrier (BBB), binding potential ratio (BPR), distribution volume (DV).
authors.affiliation: Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan. mtashiro@mail.tains.tohoku.ac.jp
authors.forename: Manabu
authors.initials: M
authors.lastname: Tashiro
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Sakurada
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishii
authors.forename: Keiichi
authors.initials: K
authors.lastname: Oda
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kimura
authors.forename: Toru
authors.initials: T
authors.lastname: Sasaki
authors.forename: Kiichi
authors.initials: K
authors.lastname: Ishiwata
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yanai
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D018592:Cross-Over Studies; D003990:Dibenzoxepins / Q000008:administration & dosage* / Q000097:blood; D004316:Doxepin; D006633:Histamine Antagonists; D006634:Histamine H1 Antagonists / Q000008:administration & dosage* / Q000097:blood; D006801:Humans; D007665:Ketotifen / Q000008:administration & dosage* / Q000097:blood; D008297:Male; D000069605:Olopatadine Hydrochloride; D049268:Positron-Emission Tomography / Q000379:methods; D011969:Receptors, Histamine H1 / Q000378:metabolism*
chemical_list: D003990:Dibenzoxepins; D006633:Histamine Antagonists; D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D004316:Doxepin; D000069605:Olopatadine Hydrochloride; D007665:Ketotifen