Brain histamine H1 receptor occupancy of orally administered antihistamines measured by positron emission tomography with 11 C-doxepin in a placebo-controlled crossover study design in healthy subjects: A comparison of olopatadine and ketotifen

Manabu Tashiro, Hideki Mochizuki, Yumiko Sakurada, Kenji Ishii, Keiichi Oda, Yuichi Kimura, Toru Sasaki, Kiichi Ishiwata, Kazuhiko Yanai

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Aims: The strength of sedation due to antihistamines can be evaluated by using positron emission tomography (PET). The purpose of the present study is to measure histamine H1 receptor (H1R) occupancy due to olopatadine, a new second-generation antihistamine and to compare it with that of ketotifen. Methods: Eight healthy males (mean age 23.5 years-old) were studied following single oral administration of olopatadine 5 mg or ketotifen 1 mg using PET with 11C-doxepin in a placebo-controlled crossover study design. Binding potential ratio and H1R occupancy were calculated and were compared between olopatadine and ketotifen in the medial prefrontal (MPFC), dorsolateral prefrontal (DLPFC), anterior cingulate (ACC), insular (IC), temporal (TC), parietal (PC), occipital cortices (OC). Plasma drug concentration was measured, and correlation of AUC to H1R occupancy was examined. Results: H1R occupancy after olopatadine treatment was significantly lower than that after ketotifen treatment in the all cortical regions (P < 0.001). Mean H1R occupancies for olopatadine and ketotifen were, respectively: MPFC, 16.7 vs. 77.7; DLPFC, 14.1 vs. 85.9; ACC, 14.7 vs. 76.1; IC, 12.8 vs. 69.7; TC, 12.5 vs. 66.5; PC, 13.9 vs. 65.8; and OC, 19.5 vs. 60.6. Overall cortical mean H1R occupancy of olopatadine and ketotifen were 15% and 72%, respectively. H1R occupancy of both drugs correlated well with their respective drug plasma concentrations (P < 0.001). Conclusion: It is suggested that 5 mg oral olopatadine, with its low H1R occupancy and thus minimal sedation, could safely be used an antiallergic treatment for various allergic disorders. Abbreviations histamine H1 receptor (H1R), histamine H1 receptor occupancy (H1RO), dopamine D2 receptor (D2R), positron emission tomography (PET), blood-brain barrier (BBB), binding potential ratio (BPR), distribution volume (DV)

Original languageEnglish (US)
Pages (from-to)16-26
Number of pages11
JournalBritish Journal of Clinical Pharmacology
Volume61
Issue number1
DOIs
StatePublished - Jan 1 2006
Externally publishedYes

Fingerprint

Doxepin
Ketotifen
Histamine H1 Receptors
Histamine Antagonists
Positron-Emission Tomography
Cross-Over Studies
Healthy Volunteers
Placebos
Brain
Occipital Lobe
Non-Sedating Histamine H1 Antagonists
Olopatadine Hydrochloride
Pharmaceutical Preparations
Anti-Allergic Agents
Dopamine D2 Receptors
Gyrus Cinguli
Blood-Brain Barrier
Area Under Curve
Oral Administration
Therapeutics

Keywords

  • First-generation antihistamine
  • Histamine H-receptor (HR)
  • Histamine H-receptor occupancy
  • Ketotifen
  • Olopatadine
  • Positron emission tomography (PET)
  • Second-generation antihistamine

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Brain histamine H1 receptor occupancy of orally administered antihistamines measured by positron emission tomography with 11 C-doxepin in a placebo-controlled crossover study design in healthy subjects : A comparison of olopatadine and ketotifen. / Tashiro, Manabu; Mochizuki, Hideki; Sakurada, Yumiko; Ishii, Kenji; Oda, Keiichi; Kimura, Yuichi; Sasaki, Toru; Ishiwata, Kiichi; Yanai, Kazuhiko.

In: British Journal of Clinical Pharmacology, Vol. 61, No. 1, 01.01.2006, p. 16-26.

Research output: Contribution to journalArticle

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abstract = "Aims: The strength of sedation due to antihistamines can be evaluated by using positron emission tomography (PET). The purpose of the present study is to measure histamine H1 receptor (H1R) occupancy due to olopatadine, a new second-generation antihistamine and to compare it with that of ketotifen. Methods: Eight healthy males (mean age 23.5 years-old) were studied following single oral administration of olopatadine 5 mg or ketotifen 1 mg using PET with 11C-doxepin in a placebo-controlled crossover study design. Binding potential ratio and H1R occupancy were calculated and were compared between olopatadine and ketotifen in the medial prefrontal (MPFC), dorsolateral prefrontal (DLPFC), anterior cingulate (ACC), insular (IC), temporal (TC), parietal (PC), occipital cortices (OC). Plasma drug concentration was measured, and correlation of AUC to H1R occupancy was examined. Results: H1R occupancy after olopatadine treatment was significantly lower than that after ketotifen treatment in the all cortical regions (P < 0.001). Mean H1R occupancies for olopatadine and ketotifen were, respectively: MPFC, 16.7 vs. 77.7; DLPFC, 14.1 vs. 85.9; ACC, 14.7 vs. 76.1; IC, 12.8 vs. 69.7; TC, 12.5 vs. 66.5; PC, 13.9 vs. 65.8; and OC, 19.5 vs. 60.6. Overall cortical mean H1R occupancy of olopatadine and ketotifen were 15{\%} and 72{\%}, respectively. H1R occupancy of both drugs correlated well with their respective drug plasma concentrations (P < 0.001). Conclusion: It is suggested that 5 mg oral olopatadine, with its low H1R occupancy and thus minimal sedation, could safely be used an antiallergic treatment for various allergic disorders. Abbreviations histamine H1 receptor (H1R), histamine H1 receptor occupancy (H1RO), dopamine D2 receptor (D2R), positron emission tomography (PET), blood-brain barrier (BBB), binding potential ratio (BPR), distribution volume (DV)",
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T1 - Brain histamine H1 receptor occupancy of orally administered antihistamines measured by positron emission tomography with 11 C-doxepin in a placebo-controlled crossover study design in healthy subjects

T2 - A comparison of olopatadine and ketotifen

AU - Tashiro, Manabu

AU - Mochizuki, Hideki

AU - Sakurada, Yumiko

AU - Ishii, Kenji

AU - Oda, Keiichi

AU - Kimura, Yuichi

AU - Sasaki, Toru

AU - Ishiwata, Kiichi

AU - Yanai, Kazuhiko

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N2 - Aims: The strength of sedation due to antihistamines can be evaluated by using positron emission tomography (PET). The purpose of the present study is to measure histamine H1 receptor (H1R) occupancy due to olopatadine, a new second-generation antihistamine and to compare it with that of ketotifen. Methods: Eight healthy males (mean age 23.5 years-old) were studied following single oral administration of olopatadine 5 mg or ketotifen 1 mg using PET with 11C-doxepin in a placebo-controlled crossover study design. Binding potential ratio and H1R occupancy were calculated and were compared between olopatadine and ketotifen in the medial prefrontal (MPFC), dorsolateral prefrontal (DLPFC), anterior cingulate (ACC), insular (IC), temporal (TC), parietal (PC), occipital cortices (OC). Plasma drug concentration was measured, and correlation of AUC to H1R occupancy was examined. Results: H1R occupancy after olopatadine treatment was significantly lower than that after ketotifen treatment in the all cortical regions (P < 0.001). Mean H1R occupancies for olopatadine and ketotifen were, respectively: MPFC, 16.7 vs. 77.7; DLPFC, 14.1 vs. 85.9; ACC, 14.7 vs. 76.1; IC, 12.8 vs. 69.7; TC, 12.5 vs. 66.5; PC, 13.9 vs. 65.8; and OC, 19.5 vs. 60.6. Overall cortical mean H1R occupancy of olopatadine and ketotifen were 15% and 72%, respectively. H1R occupancy of both drugs correlated well with their respective drug plasma concentrations (P < 0.001). Conclusion: It is suggested that 5 mg oral olopatadine, with its low H1R occupancy and thus minimal sedation, could safely be used an antiallergic treatment for various allergic disorders. Abbreviations histamine H1 receptor (H1R), histamine H1 receptor occupancy (H1RO), dopamine D2 receptor (D2R), positron emission tomography (PET), blood-brain barrier (BBB), binding potential ratio (BPR), distribution volume (DV)

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KW - Olopatadine

KW - Positron emission tomography (PET)

KW - Second-generation antihistamine

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