In:
British Journal of Clinical Pharmacology, Wiley, Vol. 52, No. 5 ( 2001-11), p. 501-509
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 H 1 ‐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, H 1 ‐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 [ 11 C]‐doxepin, a potent H 1 ‐receptor antagonist, were conducted near t max of respective drugs. Other volunteers in the control group also received PET scans. The binding potential of doxepin (BP=Bmax/ K d ) for available brain H 1 ‐receptors was imaged on a voxel‐by‐voxel basis through graphical analysis. By setting regions of interest, the H 1 ‐receptor occupancy of drugs was calculated in several H 1 ‐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 H 1 ‐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). H 1 ‐receptor occupancies in cortex were approximately 10% by ebastine and ≥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 H 1 ‐receptor occupation of approximately 10%, consistent with its lower incidence of sedative effect, whereas (+)‐chlorpheniramine occupied about 50% of brain H 1 ‐receptors even at a low but sedative dose of 2 mg; occupancy of (+)‐chlorpheniramine was correlated with plasma (+)‐chlorpheniramine concentration.
Type of Medium:
Online Resource
ISSN:
0306-5251
,
1365-2125
DOI:
10.1046/j.1365-2125.2001.01471.x
Language:
English
Publisher:
Wiley
Publication Date:
2001
detail.hit.zdb_id:
1498142-7
detail.hit.zdb_id:
188974-6
SSG:
15,3
Permalink