Brain histamine H1 receptor occupancy of a new antihistamine, bepotastine, measured by PET and [11C]doxepin

Manabu Tashiro, Duan Xudong, Motohisa Kato, Masayasu Miyake, Shouichi Watanuki, Youichi Ishikawa, Yoshihito Funaki, Ren Iwata, Masatoshi Itoh, Kazuhiko Yanai

Research output: Contribution to journalArticlepeer-review


Background and aims: Histamine H1 receptor (H1R) antagonists, or antihistamines, are often used for treatment of allergic disorders such as seasonal rhinitis. Antihistamines mainly act on the peripheral tissues but can induce sedation. This undesirable central side effect is caused by blockade of nerve transmission in the histaminergic neuron system. First-generation antihistamines such as diphenhydramine can easily penetrate blood-brain barrier (BBB) and tend to occupy a large proportion of post-synaptic H1Rs. Second-generation antihistamines such as fexofenadine and olopatadine can slightly penetrate BBB and H1Rs are slightly occupied. Thus, variation in cerebral H1R occupancy (H1RO) of antihistamines results mainly from their different BBB permeability. The aim of the present study was to compare the sedative property of a new antihistamine, bepotastine, in terms of H1RO using PET and [11C]doxepin. Methods: Eight healthy male volunteers (mean age +/- s.d.: 24.4 +/- 3.3 years old) were studied after single oral administration of bepotastine 10 mg, diphenhydramine 30 mg (a typical sedative antihistamine), or placebo, using PET and [11C]doxepin in a crossover study-design. Binding potential ratio and H1R occupancy values were calculated using placebo data, and were compared between bepotastine and diphenhydramine. PET brain images were reconstructed with a filtered back projection algorithm. The brain images were then normalized by plasma radioactivity at 10 min post-injection to yield static distribution volume (DV) images. H1RO of bepotastine was compared to that of diphenhydramine. The present study was approved by the Committee on Clinical Investigation at Tohoku University Graduate School of Medicine, Japan. All experiments were performed at the Cyclotron and Radioisotope Centre, Tohoku University. Results: Brain images following administration of bepotastine demonstrated slightly lower binding potential in comparison to those following placebo, and images following diphenhydramine administration demonstrated significantly lower binding potential in comparison to both placebo and bepotastine. Overall cortical mean H1RO of bepotastine and diphenhydramine were 15% and 57%, respectively. H1R occupancy of both bepotastine and diphenhydramine correlated well with their respective drug plasma concentration (p< 0.001). Conclusions: In the present study, H1ROs following oral administration of bepotastine 10 mg or diphenhydramine 30 mg were calculated as 14.8% and 56.8%, respectively. In our previous studies, our previous PET studies demonstrated that first-generation antihistamines occupied more than 50% of available H1Rs. The result of bepotastine (15%) is in accordance with the categorization of bepotastine as a second-generation antihistamine. Previous studies have demonstrated H1ROs of other second-generation antihistamines such as terfenadine 60 mg (12-17%), fexofenadine 120 mg (1%) and ebastine 10 mg (10%). As a whole, second-generation antihistamines seem to occupy around 0 to 20% of brain H1Rs. In conclusion, PET and [11C]doxepin is useful for evaluating sedative side effects of various psychoactive drugs with antihistamine effects. Collection of more H1RO data is encouraged for establishment of a reliable international database for evaluation of the sedative profile of psychoactive drugs.

Original languageEnglish
Pages (from-to)BP13-05M
JournalJournal of Cerebral Blood Flow and Metabolism
Issue numberSUPPL. 1
Publication statusPublished - 2007 Nov 13


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