Pharmacological profile of antihistamines: focus on unwanted drug interactions

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Differences between individual antihistamines are determined by such pharmacokinetic properties as the rate and completeness of absorption, half-life, the participation of hepatic and renal mechanisms of elimination from the body. Pharmacodynamic features of the antihistamine include selectivity and affinity for histamine H1-receptors and the presence of central effects. The mechanisms of the development of unwanted drug interactions with second-generation antihistamines are analyzed in detail. Three levels of interaction have been identified: 1) hepatic enzymes of the P450 system; 2) membrane carriers of organic anions (OATP) – transport proteins on the sinusoidal membrane of hepatocytes and the luminal membrane of the epithelium of the proximal nephron tubule; 3) P-glycoprotein (Pgp, ABCB1-protein) of epithelial cells of the small intestine – the area of absorption of oral forms of antihistamines, the epithelium of the proximal tubule and the BBB (blood-brain barrier). The emphasis is made on the description of the dependence of the pharmacological profile of antihistamines on its chemical structure. The “elasticity” of the bilastine molecule, the ability to induce a change in conformation underlies the high complementarity of bilastine to the recognition site of the H1-receptor which is a high affinity. Experimental evaluation confirms this conclusion: the dissociation constant (Dс) of the bilastin-receptor complex is in the nM concentration range. The bilastine molecule, as a representative of antihistamines with zwitterionic properties, carries both a positive and a negative charge at a physiological pH, making it difficult for its penetration into the brain. The peculiarities of the chemical nature of the bilastine molecule are reflected in the specific pharmacological profile of AGP. In vitro studies have shown a high specific affinity of bilastine for H1-receptors with a very low affinity for other histamine receptors (H2, H3, H4), serotonin, bradykinin, muscarinic and adrenergic receptors). According to this indicator, bilastine is 3 times higher than cetirizine and 5 times higher than fexofenadine. Bilastine is practically not metabolized in the body and is excreted mainly unchanged, and also does not have a cardiotoxic effect. Bilastine is well tolerated; as a therapeutic dose it has a less pronounced sedative potential compared to other second-generation antihistamines.


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About the authors

Alexander S. Dukhanin

Pirogov Russian National Research Medical University

Author for correspondence.
ORCID iD: 0000-0003-2433-7727

Professor at the Department of Molecular Pharmacology and Radiobiology, MD, PhD, Professor

Russian Federation, Moscow


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Supplementary files

Supplementary Files
1. Figure: 1. The chemical nature of the differences between AGPs of the I and II generations [2]. BBB - blood-brain barrier

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2. Figure: 2. Three main pharmacokinetic "crossroads" - the basis of the mechanisms of development of NLV

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3. Figure: 3. Contribution of various P450 isoenzymes to drug metabolism

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4. Figure: 4. Pharmacokinetic profile of II generation AGP [3]

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5. Figure: 5. The metabolic profile of bilastine. Study of the effect of bilastine (0.2–20 μm) on the activity of various isozymes of cytochrome P450 in vitro (human liver microsomes) [4]

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6. Figure: 6. Interface of the electronic drug interaction checker Drug Interactions Checker (a) and four options for presenting the results of interaction risk assessment (b). Access

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7. Figure: 7. Undesirable central effects (drowsiness) of II generation AGP [7]. NS - differences are not statistically significant

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8. Figure: 8. Dependence of the receptor occupation of the central H1 receptors and the sedative properties of AGP [8]

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9. Figure: 9. Features of the chemical structure of AGP II generation. The symbol (*) indicates an asymmetric carbon, the existence of optical isomers, including enantiomers (for cetirizine, fexofenadine); symbol (#) indicates a double bond, the presence of cis-trans isomers (olopatadin); the symbol ($) indicates a prodrug that is converted in the body into an active metabolite (loratadine, rupatadine)

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10. Figure: 10. Graphical representation of the interaction of bilastine and fexofenadine with the ligand binding domain of the H1 receptor. Molecular in silico docking of the receptor complex was performed using the method of computer simulation (CHARMm force field, Dassault Systèmes, Cedex, France)

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11. Figure: 11. The chemical nature of the differences in AGP of the second generation [8]

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