Brain histamine H1 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

Manabu Tashiro, Hideki Mochizuki, Yumiko Sakurada, Kenji Ishii, Keiichi Oda, Yuichi Kimura, Toru Sasaki, Kiichi Ishiwata, Kazuhiko Yanai

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Aims: 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 H1 receptor (H1R) 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 11C-doxepin in a placebo-controlled crossover study design. Binding potential ratio and H1R 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 H1R occupancy was examined. Results: H1R occupancy after olopatadine treatment was significantly lower than that after ketotifen treatment in the all cortical regions (P < 0.001). Mean H1R 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 H1R occupancy of olopatadine and ketotifen were 15% and 72%, respectively. H1R occupancy of both drugs correlated well with their respective drug plasma concentrations (P < 0.001). Conclusion: It is suggested that 5 mg oral olopatadine, with its low H1R occupancy and thus minimal sedation, could safely be used an antiallergic treatment for various allergic disorders. Abbreviations histamine H1 receptor (H1R), histamine H1 receptor occupancy (H1RO), dopamine D2 receptor (D2R), positron emission tomography (PET), blood-brain barrier (BBB), binding potential ratio (BPR), distribution volume (DV)

Original languageEnglish (US)
Pages (from-to)16-26
Number of pages11
JournalBritish Journal of Clinical Pharmacology
Issue number1
StatePublished - Jan 1 2006
Externally publishedYes



  • First-generation antihistamine
  • Histamine H-receptor (HR)
  • Histamine H-receptor occupancy
  • Ketotifen
  • Olopatadine
  • Positron emission tomography (PET)
  • Second-generation antihistamine

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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