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  • Title: Neuroimaging of histamine H1-receptor occupancy in human brain by positron emission tomography (PET): a comparative study of ebastine, a second-generation antihistamine, and (+)-chlorpheniramine, a classical antihistamine.
    Author: Tagawa M, Kano M, Okamura N, Higuchi M, Matsuda M, Mizuki Y, Arai H, Iwata R, Fujii T, Komemushi S, Ido T, Itoh M, Sasaki H, Watanabe T, Yanai K.
    Journal: Br J Clin Pharmacol; 2001 Nov; 52(5):501-9. PubMed ID: 11736858.
    Abstract:
    AIMS: Sedation induced by antihistamines is widely recognized to be caused by their penetration through the blood-brain-barrier and the consequent occupation of brain histamine H1-receptors. We previously studied the mechanism of sedation caused by antihistamines using positron emission tomography (PET). Recently, we revealed the nonsedative characteristic of ebastine, a second-generation antihistamine, with cognitive performance tests. In the present study, H1-receptor occupation by ebastine was examined in the human brain using PET. METHODS: Ebastine 10 mg and (+)-chlorpheniramine 2 or 6 mg were orally given to healthy male volunteers. PET scans with [11C]-doxepin, a potent H1-receptor antagonist, were conducted near tmax of respective drugs. Other volunteers in the control group also received PET scans. The binding potential of doxepin (BP = Bmax/Kd) for available brain H1-receptors was imaged on a voxel-by-voxel basis through graphical analysis. By setting regions of interest, the H1-receptor occupancy of drugs was calculated in several H1-receptor rich regions. RESULTS: Brain distribution of radioactivity after ebastine treatment was similar to that without any drugs. However, after the oral administration of 2 mg (+)-chlorpheniramine, the level was lower than after ebastine and nondrug treatments. Graphical analysis followed by statistical parametric mapping (SPM96) revealed that H1-receptor rich regions such as cortices, cingulate gyrus and thalamus were regions where the BPs after ebastine were significantly higher than after (+)-chlorpheniramine (2 mg). H1-receptor occupancies in cortex were approximately 10% by ebastine and > or = 50% by either dose of (+)-chlorpheniramine (95% confidence interval for difference in the mean receptor occupancies: 27%, 54% for 2 mg and 35%, 62% for 6 mg vs ebastine, respectively). Receptor occupancies increased with increasing plasma concentration of (+)-chlorpheniramine, but not with concentration of carebastine, an active metabolite of ebastine. CONCLUSIONS: Ebastine (10 mg orally) causes brain histamine H1-receptor occupation of approximately 10%, consistent with its lower incidence of sedative effect, whereas (+)-chlorpheniramine occupied about 50% of brain H1-receptors even at a low but sedative dose of 2 mg; occupancy of (+)-chlorpheniramine was correlated with plasma (+)-chlorpheniramine concentration.
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