Dose dependency of brain histamine H1 receptor occupancy following oral administration of cetirizine hydrochloride measured using PET with [<sup>11</sup>C]doxepin

Tashiro, Masato; Kato, Motohisa; Miyake, Masakazu; Watanuki, S.; Funaki, Y.; Ishikawa, Yoichi; Iwata, Ren; Yanai, Kazuhiko

doi:10.1002/hup.1051

Cited by 42 publications

(25 citation statements)

References 40 publications

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“…Actually, the rank order of sedative and nonsedative properties of antihistamines, which was evaluated by positron emission tomography (PET) by use of [ 11 C]doxepin in vivo (26), was not entirely identical but mostly compatible with our results: some discrepancies observed might be explained, at least in part, by the fact that the receptor occupancy by antihistamines in the brain varied according to their doses administrated (27), which resulted in changes in the rank order of their sedative and non-sedative properties in vivo (26). Thus, the assertion that sedative and non-sedative properties of antihistamines can be predominantly determined by their membrane-penetrating ability rather than their extrusion from the brain via P-glycoproteins is strengthened by the results that the QSAR model constructed on the basis of their membrane penetrating ability alone discriminated almost perfectly between sedative and non-sedative antihistamines.…”

Section: Simple Diffusion As Determinant Of Sedative and Nonsedative supporting

confidence: 79%

Molecular Determinants Responsible for Sedative and Non-sedative Properties of Histamine H1–Receptor Antagonists

2014

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Abstract. There is argument whether non-sedative properties of histamine H 1 -receptor antagonists (antihistamines) are determined by their active extrusions from the brain via P-glycoprotein or their restricted penetration through the blood-brain barrier. We have reported that sedative and non-sedative antihistamines can be well discriminated by measuring changes in their binding to H 1 receptors upon receptor internalization in intact cells, which depends on their membranepenetrating ability. In this study, molecular determinants responsible for sedative and non-sedative properties of antihistamines were evaluated by quantitative structure-activity relationship (QSAR) analyses. Multiple regression analyses were applied to construct a QSAR model, taking internalization-mediated changes in the binding of antihistamines as objective variables and their structural descriptors as explanatory variables. The multiple regression model was successfully constructed with two explanatory variables, i.e., lipophilicity of the compounds at physiological pH (logD) and mean information content on the distance degree equality (IDDE) (r 2 = 0.753). The constructed model discriminated between sedative and non-sedative antihistamines with 94% accuracy for external validation. These results suggest that logD and IDDE concerning lipophilicity and molecular shapes of compounds, respectively, predominantly determine the membranepenetrating ability of antihistamines for their side effects on the central nervous system.

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Section: Simple Diffusion As Determinant Of Sedative and Nonsedative supporting

confidence: 79%

Molecular Determinants Responsible for Sedative and Non-sedative Properties of Histamine H1–Receptor Antagonists

2014

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“…For example, positron emission tomography scanning of the human brain has shown that single oral doses of 10 and 20 mg of cetirizine caused 12.5 and 25.2% occupancy of the H 1 -receptors in prefrontal and cingulate cortices, respectively. 55 These results would explain the repeated clinical findings that the incidence of drowsiness or fatigue is greater with cetirizine than with placebo. 56 -59 Recent publications have suggested that, at manufacturer's recommended doses, levocetirizine is less sedating than cetirizine 60 and desloratadine causes negligible somnolence.…”

Section: Unwanted Effects Somnolencementioning

confidence: 96%

Pharmacology of Antihistamines

Church

2011

World Allergy Organization Journal

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This article reviews the molecular biology of the interaction of histamine with its H 1 -receptor and describes the concept that H 1 -antihistamines are not receptor antagonists but are inverse agonists i.e. they produce the opposite effect on the receptor to histamine. It then discourages the use of first-generation H 1 -antihistamines in clinical practice today for two main reasons. First, they are less effective than second generation H 1 -antihistamines. Second, they have unwanted side effects, particularly central nervous system and anti-cholinergic effects, and have the potential for causing severe toxic reactions which are not shared by second-generation H 1 -antihistamines. There are many efficacious and safe second-generation H 1 -antihistamines on the market for the treatment of allergic disease. Of the three drugs highlighted in this review, levocetirizine and fexofenadine are the most efficacious in humans in vivo. However, levocetirizine may cause somnolence in susceptible individuals while fexofenadine has a relatively short duration of action requiring twice daily administration for full all round daily protection. While desloratadine is less efficacious, it has the advantages of rarely causing somnolence and having a long duration of action. Lastly, all H 1 -antihistamines have anti-inflammatory effects but it requires regular daily dosing rather than dosing 'on-demand' for this effect to be clinically demonstrable.

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“…High H 1 -receptor occupancy is associated with decreased histaminergic neurotransmission and impaired CNS function on objective tests. [31][32][33][96][97][98] Penetration of the BBB is related to lipophilicity, relatively low molecular weight, and lack of substrate recognition by the P-glycoprotein efflux pump expressed on the luminal surfaces of nonfenestrated endothelial cells in the CNS vasculature.…”

Section: Adverse Effects Of H 1 -Antihistamines First (Old)-generatiomentioning

confidence: 99%

Histamine and H1-antihistamines: Celebrating a century of progress

Simons

2011

Journal of Allergy and Clinical Immunology

428

363

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Dose dependency of brain histamine H1 receptor occupancy following oral administration of cetirizine hydrochloride measured using PET with [¹¹C]doxepin

Abstract: It was demonstrated that the brain penetration of orally administered cetirizine was dose-dependent. Cetirizine 10 mg, with its low H(1)RO and thus minimal sedation, could be more safely used than cetirizine 20 mg for the treatment of various allergic disorders.

Cited by 42 publications

References 40 publications

Molecular Determinants Responsible for Sedative and Non-sedative Properties of Histamine H1–Receptor Antagonists

Molecular Determinants Responsible for Sedative and Non-sedative Properties of Histamine H1–Receptor Antagonists

Pharmacology of Antihistamines

Histamine and H1-antihistamines: Celebrating a century of progress

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Dose dependency of brain histamine H1 receptor occupancy following oral administration of cetirizine hydrochloride measured using PET with [11C]doxepin

Abstract: It was demonstrated that the brain penetration of orally administered cetirizine was dose-dependent. Cetirizine 10 mg, with its low H(1)RO and thus minimal sedation, could be more safely used than cetirizine 20 mg for the treatment of various allergic disorders.

Cited by 42 publications

References 40 publications

Molecular Determinants Responsible for Sedative and Non-sedative Properties of Histamine H1–Receptor Antagonists

Molecular Determinants Responsible for Sedative and Non-sedative Properties of Histamine H1–Receptor Antagonists

Pharmacology of Antihistamines

Histamine and H1-antihistamines: Celebrating a century of progress

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Product

Resources

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Dose dependency of brain histamine H1 receptor occupancy following oral administration of cetirizine hydrochloride measured using PET with [¹¹C]doxepin