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

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 signi®cantly higher than after (+)-chlorpheniramine (2 mg). H 1 -receptor occupancies in cortex were approximately 10% by ebastine and i50% by either dose of (+)-chlorpheniramine (95% con®dence 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.

Block of hERG K+ Channel by Classic Histamine H1 Receptor Antagonist Chlorpheniramine

“…The therapeutic plasma concentrations of chlorpheniramine typically range from 12.5 to 30 nM (Tagawa et al, 2001;Tagawa et al, 2002), The toxic plasma concentrations of chlorpheniramine has been shown to be 500 nM in the case report, which is ~10 times greater than the mean peak plasma level measured after a single therapeutic dose (Baselt and Cravey, 1995). Blood concentrations reported in two overdose fatalities were 1.25 and 2.75 μM (Reed, 1981;Baselt and Cravey, 1995).…”

Central Nervous System Side Effects of First- and Second-Generation Antihistamines in School Children With Perennial Allergic Rhinitis: A Randomized, Double-Blind, Placebo-Controlled Comparative Study

“…It should be noted that maximal sedation may not correlate with peak plasma drug concentration. Central H1-receptor occupancy increased significantly with increasing plasma concentration of chlorpheniramine but not with increasing concentration of the active metabolite of ebastine 39 or terfenadine. 31 We know of no such studies with cetirizine.…”

Intact Cell Binding for In Vitro Prediction of Sedative and Non-sedative Histamine H1–Receptor Antagonists Based on Receptor Internalization

“…However, the variety of chemical structures and physicochemical properties of antihistamines makes it difficult to accurately predict their ability to penetrate the biomembrane. It would greatly contribute to the development of novel antihistamines if more direct information on their membrane-penetrating properties could be obtained from a simple in vitro assay, before the use of in vivo assessments of their penetration into the brain, such as the measurement of subjective sleepiness or brain histamine H 1 -receptor occupancy using 11 C-doxepin positron emission tomography (11).…”