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Eur J Pharmacol. 2015 Oct 15;765:100-6. doi: 10.1016/j.ejphar.2015.08.016. Epub 2015 Aug 17.

Why are second-generation H1-antihistamines minimally sedating?

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Department of Biomedical Science, Iowa State University, Ames, IA, USA.
Department of Biomedical Science, Iowa State University, Ames, IA, USA. Electronic address:


H1-antihistamines are widely used in treating allergic disorders, e.g., conjunctivitis, urticaria, dermatitis and asthma. The first-generation H1-antihistamines have a much greater sedative effect than the second-generation H1-antihistamines. Researchers could not offer a satisfactory explanations until late 1990s when studies showed that second-generation H1-antihistamines were substrates of P-glycoprotein. P-glycoprotein, expressed in the blood-brain barrier, acts as an efflux pump to decrease the concentration of H1-antihistamines in the brain, which minimizes drug effects on the central nervous system and results in less sedation. P-glycoprotein is found in the apical side of the epithelium. It consists of transmembrane domains that bind substrates/drugs and nucleotide-binding domains that bind and hydrolyze ATP to generate energy for the drug efflux. This review mainly discusses interactions between P-glycoprotein and commonly used second-generation H1-antihistamines. In addition, it describes other possible determining factors of minimal sedating properties of second-generation H1-antihistamines.


H(1)-antihistamine; MDR1; Minimally sedating; P-glycoprotein; Sedative effect

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