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The role of P-glycoprotein in CNS antihistamine effects

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Abstract

Rationale

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.

Objectives

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

Methods

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.

Results

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.

Conclusion

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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Acknowledgments

We would like to thank Cees van Leeuwen for the medical supervision, Lotty Huijboom for the advice concerning the MRI measurements, and Ilja Croijmans, Emma Kremer, and Melinda Ravlic for their assistance in data collection.

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands

    Silke Conen, Eef L. Theunissen, Annemiek Vermeeren, Peter van Ruitenbeek, Peter Stiers & Johannes G. Ramaekers

  2. Neuroscience and Psychiatry Unit, Faculty of Medical and Human Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK

    Silke Conen

  3. Department of Neuroimaging, Centre for Neuroimaging Sciences, Institute of Psychiatry, King’s College London, London, UK

    Mitul A. Mehta

  4. Department of Forensic Toxicology, Institute of Legal Medicine, Goethe University of Frankfurt, Frankfurt, Germany

    Stefan W. Toennes

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  1. Silke Conen
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  2. Eef L. Theunissen
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  3. Annemiek Vermeeren
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  4. Peter van Ruitenbeek
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  5. Peter Stiers
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  8. Johannes G. Ramaekers
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Corresponding author

Correspondence to Silke Conen.

Additional information

This trial has been registered at www.trialregister.nl as NTR2609, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2609.

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Conen, S., Theunissen, E.L., Vermeeren, A. et al. The role of P-glycoprotein in CNS antihistamine effects. Psychopharmacology 229, 9–19 (2013). https://doi.org/10.1007/s00213-013-3075-z

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  • DOI: https://doi.org/10.1007/s00213-013-3075-z

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