Binding of chlorpheniramine enantiomers to human plasma proteins

Hiep, Bui Tung; Gimenez, François; Khanh, Vu; Hung, Nguyen Kim; Thuillier, A.; Farinotti, Robert; Fernandez, Christine

doi:10.1002/(sici)1520-636x(1999)11:5/6<501::aid-chir24>3.3.co;2-b

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“…Dotted curves shown in Figure 4 were ®tted by analysis of H 1 -receptor occupancy and the plasma concentration using Michaelis±Menten model (assuming the maximum of H 1 -receptor occupancy as 100%). Consequently, apparent K d values (dissociation equilibrium constant) of (+)-chlorpheniramine for H 1 plasma concentration of (+)-chlorpheniramine assuming that its plasma protein binding was 32% [27]. Since the free drug concentration in plasma is equal to that in the tissue (brain), the calculated mean K d value of about 7 nM could be the intrinsic K d value of (+)-chlorpheniramine for brain H 1 -receptors.…”

Section: Discussionmentioning

confidence: 99%

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

Tagawa¹,

Kano²,

Okamura

et al. 2001

Brit J Clinical Pharma

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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.

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Section: Discussionmentioning

confidence: 99%

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

Tagawa¹,

Kano²,

Okamura

et al. 2001

Brit J Clinical Pharma

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“…Chiral amylose AD columns have also been employed in the enantioselective analysis of the concentrations of disopyramide, tramadol, chlorpheniramine, and their corresponding active metabolites. 58,61 The methods developed for each drug and its metabolites have been validated and their clinical relevance has been confirmed in pharmacokinetic studies performed in healthy volunteers.…”

Section: Applications Of Stereoselective Chromatography In Clinical Pmentioning

confidence: 99%

Recent applications of stereoselective chromatography

2002

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Binding of chlorpheniramine enantiomers to human plasma proteins

Cited by 2 publications

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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

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

Recent applications of stereoselective chromatography

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Binding of chlorpheniramine enantiomers to human plasma proteins

Cited by 2 publications

References 0 publications

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

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

Recent applications of stereoselective chromatography

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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

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