Relationship between MDR-1 polymorphism and brain penetration of fexofenadine, an antihistamine, evaluated by PET with [11C]doxepin

Manabu Tashiro, Masayuki Tsujimoto, Motohisa Kato, Hisakazu Ohtani, Masatoshi Itoh, Yasufumi Sawada, Kazuhiko Yanai

Research output: Contribution to journalArticle

Abstract

Background and aims: Histamine H1 receptor (H1R) antagonists, or antihistamines, mainly act on the peripheral tissues but can induce sedation. This undesirable central side effect is caused by blockade of nerve transmission in the histaminergic neuron system. Variation in sedative properties of antihistamines is due to difference in their blood-brain barrier (BBB) permeability, partly defined by activity of P-glycoprotein (P-gp), an efflux pump located in the membrane of endothelial cells in brain capillaries. The aim of the present study is to evaluate the effects of single nucleotide polymorphisms (SNP) of the P-gp encoding "multi-drug resistance gene (MDR)-1" on BBB permeability of a non-sedative antihistamine, fexofenadine, that is a substrate of P-gp, using positron emission tomography (PET) with [11C]doxepin. Methods: Healthy young male volunteers (n=39, ranging 19-36 y.o.) were recruited and examined for genotyping of the common SNP in exon 26 (C3435T). Twenty-two out of the 39 subjects were studied by PET with [11C]doxepin following oral administration of placebo or fexofenadine 120 mg, in a single blind cross-over design. PET scan started 90 min following administration of each drug and the dynamic data, obtained taking 90 min, were analyzed based on Logan reference method to yield binding potential in various cortical structures. Based on the biding potential data of each subject in two drug conditions, histamine H1 receptor occupancy (H1RO) due to fexofenadine was calculated for each subject and the individual H1RO values were compared between wild-type (CC: n=6), heterozygous (CT: n=13) and homozygous (TT: n=3) subgroups. Results: Overall mean H1RO due to fexofenadine in the 22 subjects was calculated as -5%. The mean H1ROs of the 3 subgroups, CC, CT and TT, were -13.4, -3.7 and -1.4%, respectively, although the difference was not significant. Conclusions: The reason that H1RO of fexofenadine was calculated as lower than zero is not known. The PET results might suggest the presence of slight decrease in efflux function of P-glycoprotein in BBB among holders of C3435T mutation in comparison to wild-type in human. Further investigation is needed to draw a definitive conclusion with larger sample size, including studies on other mutations and other influx and efflux transporters. Functional and molecular imaging will be a strong tool for establishment of "individualized medicine".

Original languageEnglish
JournalJournal of Cerebral Blood Flow and Metabolism
Volume27
Issue numberSUPPL. 1
Publication statusPublished - 2007 Nov 13
Externally publishedYes

Fingerprint

fexofenadine
Doxepin
Histamine Antagonists
Multiple Drug Resistance
Histamine H1 Receptors
Positron-Emission Tomography
P-Glycoprotein
Blood-Brain Barrier
Brain
Genes
Single Nucleotide Polymorphism
Permeability
Histamine H1 Antagonists
Precision Medicine
Mutation
Molecular Imaging
Nerve Block
Hypnotics and Sedatives
Pharmaceutical Preparations
Sample Size

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

Cite this

Relationship between MDR-1 polymorphism and brain penetration of fexofenadine, an antihistamine, evaluated by PET with [11C]doxepin. / Tashiro, Manabu; Tsujimoto, Masayuki; Kato, Motohisa; Ohtani, Hisakazu; Itoh, Masatoshi; Sawada, Yasufumi; Yanai, Kazuhiko.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 27, No. SUPPL. 1, 13.11.2007.

Research output: Contribution to journalArticle

Tashiro, Manabu ; Tsujimoto, Masayuki ; Kato, Motohisa ; Ohtani, Hisakazu ; Itoh, Masatoshi ; Sawada, Yasufumi ; Yanai, Kazuhiko. / Relationship between MDR-1 polymorphism and brain penetration of fexofenadine, an antihistamine, evaluated by PET with [11C]doxepin. In: Journal of Cerebral Blood Flow and Metabolism. 2007 ; Vol. 27, No. SUPPL. 1.
@article{50e4b462229e4be2b60a63a5a0fbf35f,
title = "Relationship between MDR-1 polymorphism and brain penetration of fexofenadine, an antihistamine, evaluated by PET with [11C]doxepin",
abstract = "Background and aims: Histamine H1 receptor (H1R) antagonists, or antihistamines, mainly act on the peripheral tissues but can induce sedation. This undesirable central side effect is caused by blockade of nerve transmission in the histaminergic neuron system. Variation in sedative properties of antihistamines is due to difference in their blood-brain barrier (BBB) permeability, partly defined by activity of P-glycoprotein (P-gp), an efflux pump located in the membrane of endothelial cells in brain capillaries. The aim of the present study is to evaluate the effects of single nucleotide polymorphisms (SNP) of the P-gp encoding {"}multi-drug resistance gene (MDR)-1{"} on BBB permeability of a non-sedative antihistamine, fexofenadine, that is a substrate of P-gp, using positron emission tomography (PET) with [11C]doxepin. Methods: Healthy young male volunteers (n=39, ranging 19-36 y.o.) were recruited and examined for genotyping of the common SNP in exon 26 (C3435T). Twenty-two out of the 39 subjects were studied by PET with [11C]doxepin following oral administration of placebo or fexofenadine 120 mg, in a single blind cross-over design. PET scan started 90 min following administration of each drug and the dynamic data, obtained taking 90 min, were analyzed based on Logan reference method to yield binding potential in various cortical structures. Based on the biding potential data of each subject in two drug conditions, histamine H1 receptor occupancy (H1RO) due to fexofenadine was calculated for each subject and the individual H1RO values were compared between wild-type (CC: n=6), heterozygous (CT: n=13) and homozygous (TT: n=3) subgroups. Results: Overall mean H1RO due to fexofenadine in the 22 subjects was calculated as -5{\%}. The mean H1ROs of the 3 subgroups, CC, CT and TT, were -13.4, -3.7 and -1.4{\%}, respectively, although the difference was not significant. Conclusions: The reason that H1RO of fexofenadine was calculated as lower than zero is not known. The PET results might suggest the presence of slight decrease in efflux function of P-glycoprotein in BBB among holders of C3435T mutation in comparison to wild-type in human. Further investigation is needed to draw a definitive conclusion with larger sample size, including studies on other mutations and other influx and efflux transporters. Functional and molecular imaging will be a strong tool for establishment of {"}individualized medicine{"}.",
author = "Manabu Tashiro and Masayuki Tsujimoto and Motohisa Kato and Hisakazu Ohtani and Masatoshi Itoh and Yasufumi Sawada and Kazuhiko Yanai",
year = "2007",
month = "11",
day = "13",
language = "English",
volume = "27",
journal = "Journal of Cerebral Blood Flow and Metabolism",
issn = "0271-678X",
publisher = "Nature Publishing Group",
number = "SUPPL. 1",

}

TY - JOUR

T1 - Relationship between MDR-1 polymorphism and brain penetration of fexofenadine, an antihistamine, evaluated by PET with [11C]doxepin

AU - Tashiro, Manabu

AU - Tsujimoto, Masayuki

AU - Kato, Motohisa

AU - Ohtani, Hisakazu

AU - Itoh, Masatoshi

AU - Sawada, Yasufumi

AU - Yanai, Kazuhiko

PY - 2007/11/13

Y1 - 2007/11/13

N2 - Background and aims: Histamine H1 receptor (H1R) antagonists, or antihistamines, mainly act on the peripheral tissues but can induce sedation. This undesirable central side effect is caused by blockade of nerve transmission in the histaminergic neuron system. Variation in sedative properties of antihistamines is due to difference in their blood-brain barrier (BBB) permeability, partly defined by activity of P-glycoprotein (P-gp), an efflux pump located in the membrane of endothelial cells in brain capillaries. The aim of the present study is to evaluate the effects of single nucleotide polymorphisms (SNP) of the P-gp encoding "multi-drug resistance gene (MDR)-1" on BBB permeability of a non-sedative antihistamine, fexofenadine, that is a substrate of P-gp, using positron emission tomography (PET) with [11C]doxepin. Methods: Healthy young male volunteers (n=39, ranging 19-36 y.o.) were recruited and examined for genotyping of the common SNP in exon 26 (C3435T). Twenty-two out of the 39 subjects were studied by PET with [11C]doxepin following oral administration of placebo or fexofenadine 120 mg, in a single blind cross-over design. PET scan started 90 min following administration of each drug and the dynamic data, obtained taking 90 min, were analyzed based on Logan reference method to yield binding potential in various cortical structures. Based on the biding potential data of each subject in two drug conditions, histamine H1 receptor occupancy (H1RO) due to fexofenadine was calculated for each subject and the individual H1RO values were compared between wild-type (CC: n=6), heterozygous (CT: n=13) and homozygous (TT: n=3) subgroups. Results: Overall mean H1RO due to fexofenadine in the 22 subjects was calculated as -5%. The mean H1ROs of the 3 subgroups, CC, CT and TT, were -13.4, -3.7 and -1.4%, respectively, although the difference was not significant. Conclusions: The reason that H1RO of fexofenadine was calculated as lower than zero is not known. The PET results might suggest the presence of slight decrease in efflux function of P-glycoprotein in BBB among holders of C3435T mutation in comparison to wild-type in human. Further investigation is needed to draw a definitive conclusion with larger sample size, including studies on other mutations and other influx and efflux transporters. Functional and molecular imaging will be a strong tool for establishment of "individualized medicine".

AB - Background and aims: Histamine H1 receptor (H1R) antagonists, or antihistamines, mainly act on the peripheral tissues but can induce sedation. This undesirable central side effect is caused by blockade of nerve transmission in the histaminergic neuron system. Variation in sedative properties of antihistamines is due to difference in their blood-brain barrier (BBB) permeability, partly defined by activity of P-glycoprotein (P-gp), an efflux pump located in the membrane of endothelial cells in brain capillaries. The aim of the present study is to evaluate the effects of single nucleotide polymorphisms (SNP) of the P-gp encoding "multi-drug resistance gene (MDR)-1" on BBB permeability of a non-sedative antihistamine, fexofenadine, that is a substrate of P-gp, using positron emission tomography (PET) with [11C]doxepin. Methods: Healthy young male volunteers (n=39, ranging 19-36 y.o.) were recruited and examined for genotyping of the common SNP in exon 26 (C3435T). Twenty-two out of the 39 subjects were studied by PET with [11C]doxepin following oral administration of placebo or fexofenadine 120 mg, in a single blind cross-over design. PET scan started 90 min following administration of each drug and the dynamic data, obtained taking 90 min, were analyzed based on Logan reference method to yield binding potential in various cortical structures. Based on the biding potential data of each subject in two drug conditions, histamine H1 receptor occupancy (H1RO) due to fexofenadine was calculated for each subject and the individual H1RO values were compared between wild-type (CC: n=6), heterozygous (CT: n=13) and homozygous (TT: n=3) subgroups. Results: Overall mean H1RO due to fexofenadine in the 22 subjects was calculated as -5%. The mean H1ROs of the 3 subgroups, CC, CT and TT, were -13.4, -3.7 and -1.4%, respectively, although the difference was not significant. Conclusions: The reason that H1RO of fexofenadine was calculated as lower than zero is not known. The PET results might suggest the presence of slight decrease in efflux function of P-glycoprotein in BBB among holders of C3435T mutation in comparison to wild-type in human. Further investigation is needed to draw a definitive conclusion with larger sample size, including studies on other mutations and other influx and efflux transporters. Functional and molecular imaging will be a strong tool for establishment of "individualized medicine".

UR - http://www.scopus.com/inward/record.url?scp=36348953092&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=36348953092&partnerID=8YFLogxK

M3 - Article

AN - SCOPUS:36348953092

VL - 27

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

SN - 0271-678X

IS - SUPPL. 1

ER -