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.
OBJECTIVE
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.
Tagawa
M
M
Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan.
Kano
M
M
Okamura
N
N
Higuchi
M
M
Matsuda
M
M
Mizuki
Y
Y
Arai
H
H
Iwata
R
R
Fujii
T
T
Komemushi
S
S
Ido
T
T
Itoh
M
M
Sasaki
H
H
Watanabe
T
T
Yanai
K
K
D000328:Adult; D002090:Butyrophenones / Q000378:metabolism / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D002540:Cerebral Cortex / Q000187:drug effects*; D002744:Chlorpheniramine / Q000378:metabolism / Q000494:pharmacology*; D018592:Cross-Over Studies; D006634:Histamine H1 Antagonists / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008954:Models, Biological; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D011969:Receptors, Histamine H1 / Q000187:drug effects*; D016037:Single-Blind Method; D013788:Thalamus / Q000187:drug effects; D014055:Tomography, Emission-Computed; D016896:Treatment Outcome
D002090:Butyrophenones; D002250:Carbon Radioisotopes; D006634:Histamine H1 Antagonists; D010880:Piperidines; D011969:Receptors, Histamine H1; D002744:Chlorpheniramine; C058249:ebastine