The role of P-glycoprotein in CNS antihistamine effects

Silke Conen; Eef L. Theunissen; Annemiek Vermeeren; Peter van Ruitenbeek; Peter Stiers; Mitul A. Mehta; Stefan W. Toennes; Johannes G. Ramaekers

doi:10.1007/s00213-013-3075-z

The role of P-glycoprotein in CNS antihistamine effects

Silke Conen^*, Eef L. Theunissen, Annemiek Vermeeren, Peter van Ruitenbeek, Peter Stiers, Mitul A. Mehta, Stefan W. Toennes, Johannes G. Ramaekers

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

Abstract

P-glycoprotein (P-gp) is a drug efflux pump expressed, amongst others, on the luminal surface of the cerebral endothelial cells forming the blood-brain barrier. Studies in rodents have demonstrated that antihistamines that are substrates of the P-gp transporter display no or minor central nervous system (CNS) effects as compared to antihistamines that are not P-gp transporter substrates.

The present study explored whether P-gp contributes in similar ways to the occurrence of sedative effects of antihistamines in humans.

An fMRI study was conducted according to a double-blind, randomized, placebo-controlled, cross-over design in 13 healthy volunteers. Participants received cetirizine 15 mg (an antihistamine), verapamil 120 mg (a P-gp blocker), a combination of cetirizine + verapamil, and a placebo. Brain activity was assessed while conducting the attention network test (ANT) in a 3T magnetic resonance scanner. The ANT measures three independent attention domains: i.e., alerting, orienting, and executive attention. It was expected that the combined treatment of cetirizine with verapamil would prevent efflux of cetirizine from the CNS, thus increasing attentional impairment, as compared to cetirizine administered alone.

The present study provides evidence that the P-gp transporter is involved in central antihistamine effects in humans. Participants were less alert during the combined treatment of cetirizine and verapamil as indicated by longer reaction times and decreased blood oxygen level-dependent response in the right superior temporal gyrus.

It is concluded that the affinity for the P-gp transporter may contribute to the lower incidence of CNS side effects of certain antihistamines.

Original language	English
Article number	N/A
Pages (from-to)	9-19
Number of pages	11
Journal	Psychopharmacology
Volume	229
Issue number	1
DOIs	https://doi.org/10.1007/s00213-013-3075-z
Publication status	Published - Sept 2013

Keywords

Attention
Behavior
Blood-brain barrier
Brain imaging
CNS
Cognition
fMRI
P-glycoprotein
Histamine
Receptor binding
BLOOD-BRAIN-BARRIER
HYDROXYZINE 50 MG
PSYCHOMOTOR PERFORMANCE
ATTENTIONAL NETWORKS
DRIVING PERFORMANCE
HEALTHY-VOLUNTEERS
CYTOCHROME-P450 ENZYMES
H1-RECEPTOR ANTAGONIST
FEXOFENADINE
CETIRIZINE

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10.1007/s00213-013-3075-z

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title = "The role of P-glycoprotein in CNS antihistamine effects",

abstract = "P-glycoprotein (P-gp) is a drug efflux pump expressed, amongst others, on the luminal surface of the cerebral endothelial cells forming the blood-brain barrier. Studies in rodents have demonstrated that antihistamines that are substrates of the P-gp transporter display no or minor central nervous system (CNS) effects as compared to antihistamines that are not P-gp transporter substrates.The present study explored whether P-gp contributes in similar ways to the occurrence of sedative effects of antihistamines in humans.An fMRI study was conducted according to a double-blind, randomized, placebo-controlled, cross-over design in 13 healthy volunteers. Participants received cetirizine 15 mg (an antihistamine), verapamil 120 mg (a P-gp blocker), a combination of cetirizine + verapamil, and a placebo. Brain activity was assessed while conducting the attention network test (ANT) in a 3T magnetic resonance scanner. The ANT measures three independent attention domains: i.e., alerting, orienting, and executive attention. It was expected that the combined treatment of cetirizine with verapamil would prevent efflux of cetirizine from the CNS, thus increasing attentional impairment, as compared to cetirizine administered alone.The present study provides evidence that the P-gp transporter is involved in central antihistamine effects in humans. Participants were less alert during the combined treatment of cetirizine and verapamil as indicated by longer reaction times and decreased blood oxygen level-dependent response in the right superior temporal gyrus.It is concluded that the affinity for the P-gp transporter may contribute to the lower incidence of CNS side effects of certain antihistamines.",

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author = "Silke Conen and Theunissen, {Eef L.} and Annemiek Vermeeren and {van Ruitenbeek}, Peter and Peter Stiers and Mehta, {Mitul A.} and Toennes, {Stefan W.} and Ramaekers, {Johannes G.}",

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doi = "10.1007/s00213-013-3075-z",

language = "English",

volume = "229",

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journal = "Psychopharmacology",

issn = "0033-3158",

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T1 - The role of P-glycoprotein in CNS antihistamine effects

AU - Conen, Silke

AU - Theunissen, Eef L.

AU - Vermeeren, Annemiek

AU - van Ruitenbeek, Peter

AU - Stiers, Peter

AU - Mehta, Mitul A.

AU - Toennes, Stefan W.

AU - Ramaekers, Johannes G.

PY - 2013/9

Y1 - 2013/9

N2 - P-glycoprotein (P-gp) is a drug efflux pump expressed, amongst others, on the luminal surface of the cerebral endothelial cells forming the blood-brain barrier. Studies in rodents have demonstrated that antihistamines that are substrates of the P-gp transporter display no or minor central nervous system (CNS) effects as compared to antihistamines that are not P-gp transporter substrates.The present study explored whether P-gp contributes in similar ways to the occurrence of sedative effects of antihistamines in humans.An fMRI study was conducted according to a double-blind, randomized, placebo-controlled, cross-over design in 13 healthy volunteers. Participants received cetirizine 15 mg (an antihistamine), verapamil 120 mg (a P-gp blocker), a combination of cetirizine + verapamil, and a placebo. Brain activity was assessed while conducting the attention network test (ANT) in a 3T magnetic resonance scanner. The ANT measures three independent attention domains: i.e., alerting, orienting, and executive attention. It was expected that the combined treatment of cetirizine with verapamil would prevent efflux of cetirizine from the CNS, thus increasing attentional impairment, as compared to cetirizine administered alone.The present study provides evidence that the P-gp transporter is involved in central antihistamine effects in humans. Participants were less alert during the combined treatment of cetirizine and verapamil as indicated by longer reaction times and decreased blood oxygen level-dependent response in the right superior temporal gyrus.It is concluded that the affinity for the P-gp transporter may contribute to the lower incidence of CNS side effects of certain antihistamines.

AB - P-glycoprotein (P-gp) is a drug efflux pump expressed, amongst others, on the luminal surface of the cerebral endothelial cells forming the blood-brain barrier. Studies in rodents have demonstrated that antihistamines that are substrates of the P-gp transporter display no or minor central nervous system (CNS) effects as compared to antihistamines that are not P-gp transporter substrates.The present study explored whether P-gp contributes in similar ways to the occurrence of sedative effects of antihistamines in humans.An fMRI study was conducted according to a double-blind, randomized, placebo-controlled, cross-over design in 13 healthy volunteers. Participants received cetirizine 15 mg (an antihistamine), verapamil 120 mg (a P-gp blocker), a combination of cetirizine + verapamil, and a placebo. Brain activity was assessed while conducting the attention network test (ANT) in a 3T magnetic resonance scanner. The ANT measures three independent attention domains: i.e., alerting, orienting, and executive attention. It was expected that the combined treatment of cetirizine with verapamil would prevent efflux of cetirizine from the CNS, thus increasing attentional impairment, as compared to cetirizine administered alone.The present study provides evidence that the P-gp transporter is involved in central antihistamine effects in humans. Participants were less alert during the combined treatment of cetirizine and verapamil as indicated by longer reaction times and decreased blood oxygen level-dependent response in the right superior temporal gyrus.It is concluded that the affinity for the P-gp transporter may contribute to the lower incidence of CNS side effects of certain antihistamines.

KW - Attention

KW - Behavior

KW - Blood-brain barrier

KW - Brain imaging

KW - CNS

KW - Cognition

KW - fMRI

KW - P-glycoprotein

KW - Histamine

KW - Receptor binding

KW - BLOOD-BRAIN-BARRIER

KW - HYDROXYZINE 50 MG

KW - PSYCHOMOTOR PERFORMANCE

KW - ATTENTIONAL NETWORKS

KW - DRIVING PERFORMANCE

KW - HEALTHY-VOLUNTEERS

KW - CYTOCHROME-P450 ENZYMES

KW - H1-RECEPTOR ANTAGONIST

KW - FEXOFENADINE

KW - CETIRIZINE

U2 - 10.1007/s00213-013-3075-z

DO - 10.1007/s00213-013-3075-z

M3 - Article

SN - 0033-3158

VL - 229

SP - 9

EP - 19

JO - Psychopharmacology

JF - Psychopharmacology

IS - 1

M1 - N/A

ER -

The role of P-glycoprotein in CNS antihistamine effects

Abstract

Keywords

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