Abstract
Introduction. Allergic bronchial asthma (BA) is accompanied by activation of histamine H1/H4 receptors and variable response to antihistamines.
The aim of this review is to analyze the molecular mechanisms of action of second- and third-generation antihistamine drugs, their pharmacokinetic features and pharmacogenetic aspects of application in bronchial asthma, as well as prospects for developing new drugs with improved characteristics.
Methods. Narrative review of the literature (PubMed/Scopus, 2019–2024), including data from cryo-EM structures of the H4 receptor, single-cell RNA-seq profiles of bronchial epithelium and clinical pharmacogenetic studies of the CYP family (41 sources).
Results. Key signaling pathways (FcεRI–MAPK/NF-κB, IL-13/STAT6) indirectly targeted by H1 blockers have been identified. Increased HRH4 expression in IL-13^high Th2 clusters has been shown to correlate with asthma severity. Modern cryo-EM models of H4R have allowed us to refine the architecture of binding sites and optimize the design of promising ligands. CYP2D6 and ABCB1 polymorphisms account for up to 30–50% of interindividual variability in plasma concentrations of loratadine/desloratadine and bilastine according to clinical cohort data.
Conclusion. Integration of omics data and pharmacogenetic testing opens the way to targeted and personalized asthma therapy with antihistamines.
Keywords
Authors and affiliations
E.A. Borodulina(1), E.V. Yakovleva(1), B.E. Borodulin(1), E.P. Gladunova(1), S.D. Marchenko(2),
O.V. Krylova(2), E.R. Mamontova(3), A.R. Rekalo(3), Z.R. Minnullina (3), B.R. Bagirova(4), A.A. Salpagarova(4)
1-Federal State Budgetary Educational Institution of Higher Education “Samara State Medical University” of the Ministry of Healthcare of the Russian Federation, Chapaevskaya, 99, Samara, 443099, Russian Federation; 2-Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation
(Sechenov University), Trubetskaya str., 8, build. 2, Moscow, 119991, Russian Federation; 3-Federal State Autonomous Educational Institution of Higher Education “Russian National Research Medical University named after N.I. Pirogov” of the Ministry of Health
of the Russian Federation, Ostrovityanova str., 1, Moscow, 117997, Russian Federation; 4-Federal State Budgetary Educational
Institution of Higher Education “North Caucasian State Academy”, Medical Institute, Stavropolskaya St., 36, Cherkessk,
Karachay-Cherkess Republic, 369001, Russian Federation
References
Lambrecht B.N., Hammad H. The immunology of asthma. Nat Immunol. 2015; 16 (1): 45–56. doi: 10.1038/ni.3049
Al-Maamari A., Sultan M., Ding S., Yuxin D., Wang M.Y., Su S. Mechanisms and implications of histamine-induced reactions and complications. Allergol Immunopathol (Madr). 2025; 53 (3): 122–39. doi: 10.15586/aei.v53i3.1272
Tiligada E., Stefanaki C., Ennis M., Neumann D. Opportunities and challenges in the therapeutic exploitation of histamine and histamine receptor pharmacology in inflammation-driven disorders. Pharmacol Ther. 2024; 263: 108722. doi: 10.1016/j.pharmthera.2024.108722
Simons F.E., Simons K.J. Histamine and H1-antihistamines: celebrating a century of progress. J. Allergy Clin Immunol. 2011; 128 (6): 1139–50.e4. doi: 10.1016/j.jaci.2011.09.005
Thurmond R.L., Gelfand E.W., Dunford P.J. The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines. Nat Rev Drug Discov. 2008; 7 (1): 41–53. doi: 10.1038/nrd2465
Nikolouli E., Mommert S., Dawodu D.M. et al. The stimulation of TH2 cells results in increased IL-5 and IL-13 production via the H4 receptor. Allergy. 2024; 79 (8): 2186–96. doi: 10.1111/all.16182
Xia, R., Shi, S., Xu, Z. et al. Structural basis of ligand recognition and design of antihistamines targeting histamine H4 receptor. Nat Commun. 2024; 15: 2493. https://doi.org/10.1038/s41467-024-46840-5
Staub A.M., Bovet D. Action de la thymoxyethyldiethylamine (925 F) et des ethers phenoliquers sur le choc anaphylactique du cobaye. Compt Rend Soc Biol. 1937; 125: 818–23.
Church M.K., Church D.S. Pharmacology of antihistamines. Indian J. Dermatol. 2013; 58 (3): 219–24. DOI: 10.4103/0019-5154.110832
Galli S.J., Tsai M. IgE and mast cells in allergic disease. Nat Med. 2012; 18 (5): 693–704. DOI: 10.1038/nm.2755
Ahmad S., Israf D.A., Lajis N.H. et al. Cardamonin, inhibits pro-inflammatory mediators in activated RAW 264.7 cells and whole blood. Eur. J. Pharmacol. 2006; 538 (1–3): 188–94. doi: 10.1016/j.ejphar.2006.03.070
Song Y., Qu R., Zhu S., Zhang R., Ma S. Rhynchophylline attenuates LPS-induced pro-inflammatory responses through down-regulation of MAPK/NF-κB signaling pathways in primary microglia. Phytother Res. 2012; 26 (10): 1528–33. doi: 10.1002/ptr.4614
Goenka S., Kaplan M.H. Transcriptional regulation by STAT6. Immunol Res. 2011; 50 (1): 87–96. doi: 10.1007/s12026-011-8205-2
Tillement J.P., Testa B., Brée F. Compared pharmacological characteristics in humans of racemic cetirizine and levocetirizine, two histamine H1-receptor antagonists. Biochem Pharmacol. 2003; 66 (7): 1123–6. doi: 10.1016/s0006-2952(03)00558-6
Sánchez-Borges M., Caballero-Fonseca F., Capriles-Hulett A., González-Aveledo L. Hypersensitivity reactions to non-steroidal anti-inflammatory drugs: an update. Pharmaceuticals (Basel). 2010; 3 (1): 10–8. doi: 10.3390/ph3010010
Molimard M., Diquet B., Benedetti M.S. Comparison of pharmacokinetics and metabolism of desloratadine, fexofenadine, levocetirizine and mizolastine in humans. Fundam Clin Pharmacol. 2004; 18 (4): 399–411. doi: 10.1111/j.1472-8206.2004.00254.x
Polli J.W., Baughman T.M., Humphreys J.E. et al. P-glycoprotein influences the brain concentrations of cetirizine (Zyrtec), a second-generation non-sedating antihistamine. J. Pharm Sci. 2003; 92 (10): 2082–9. doi: 10.1002/jps.10453
Wang Y.H., Cai L. Pharmacogenomics-guided advances in antihistamine therapy. Clin Rev Allergy Immunol. 2021; 61 (3): 293–309. doi: 10.1007/s12016-021-08851-8
Li Q, Wu YE, Wang K, Shi HY, Zhou Y, Zheng Y, Hao GX, Yang YL, Su LQ, Wang WQ, Yang XM, Zhao W. Developmental Pharmacogenetics of CYP2D6 in Chinese Children: Loratadine as a Substrate Drug. Front Pharmacol. 2021; 12: 657287. DOI: 10.3389/fphar.2021.657287. PMID: 34295246; PMCID: PMC8292113.
. De Sutter A.I., Saraswat A., van Driel M.L. Antihistamines for the common cold. Cochrane Database Syst Rev. 2015; 2015 (11): CD009345. DOI: 10.1002/14651858.CD009345.pub2
. Garcia-Erce P., et al. Multi-omics endotyping of allergic asthma reveals histamine receptor pathway heterogeneity. Front Immunol. 2022; 13: 988573. DOI: 10.3389/fimmu.2022.988573
. Strother R.M., et al. Point-of-care pharmacogenomics implementation in clinical decision support systems. Clin Pharmacol Ther. 2023; 113 (4): 891–9. DOI: 10.1002/cpt.2876
. Rajasekhar K., et al. Structural insights into H4 receptor-selective antagonists and their therapeutic potential. Br. J. Pharmacol. 2024; 181 (8): 1234–48. DOI: 10.1111/bph.15999Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J. 2005; 5 (1): 6–13. DOI: 10.1038/sj.tpj.6500285
. Dresser G.K., Bailey D.G., Leake B.F. et al. Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther. 2002; 71 (1): 11–20. DOI: 10.1067/mcp.2002.121152
. Devillier P., Roche N., Faisy C. Clinical pharmacokinetics and pharmacodynamics of desloratadine, fexofenadine and levocetirizine: a comparative review. Clin Pharmacokinet. 2008; 47 (4): 217–30. DOI: 10.2165/00003088-200847040-00001
Preuss C.V., Wood T.C., Szumlanski C.L. et al. Human histamine N-methyltransferase pharmacogenetics: common genetic polymorphisms that alter activity. Mol Pharmacol. 1998; 53 (4): 708–17. DOI: 10.1124/mol.53.4.708
Zhang M., Thurmond R.L., Dunford P.J. The histamine H(4) receptor: a novel modulator of inflammatory and immune disorders. Pharmacol Ther. 2007; 113 (3): 594–606. DOI: 10.1016/j.pharmthera.2006.11.008
. Saglam-Сifci E., Güleç İ., Şengelen A. et al. The H4R antagonist, JNJ-7777120 treatments ameliorate mild traumatic brain injury by reducing oxidative damage, inflammatory and apoptotic responses through blockage of the ERK1/2/NF-κB pathway in a rat model. Exp Neurol. 2025; 385: 115133. DOI: 10.1016/j.expneurol.2024.115133
Karcz T., Szczepanska K., Mogilski S. et al. Guanidine Derivative ADS1017, a Potent Histamine H(3) Receptor Antagonist with Promising Analgesic Activity and Satisfactory Safety Profile. ACS Chem Neurosci. 2024; 15 (24): 4441–57. DOI: 10.1021/acschemneuro.4c00480
Jin B.H., Hong T., Yoo B.W. et al. Pharmacokinetics, pharmacodynamics, and safety of izuforant, an H4R inhibitor, in healthy subjects: A phase I single and multiple ascending dose study. Clin Transl Sci. 2024; 17 (10): e70032. DOI: 10.1111/cts.70032
Kwon J.W., Lee K., Kim S.W. et al. Therapeutic potential of histamine H(4) receptor antagonist as a preventive treatment for diabetic retinopathy in mice. Sci Rep. 2024; 14 (1): 22664. DOI: 10.1038/s41598-024-72166-9
Stasiak A., Honkisz-Orzechowska E., Gajda Z. et al. AR71, Histamine H(3) Receptor Ligand-In Vitro and In Vivo Evaluation (Anti-Inflammatory Activity, Metabolic Stability, Toxicity, and Analgesic Action). Int. J. Mol. Sci. 2024; 25 (15): 8035. DOI: 10.3390/ijms25158035
Dunford P.J., O’Donnell N., Riley J.P. et al. The histamine H4 receptor mediates allergic airway inflammation by regulating the activation of CD4+ T cells. J. Immunol. 2006; 176 (11): 7062–70. DOI: 10.4049/jimmunol.176.11.7062
Coruzzi G., Adami M., Guaita E. et al. Antiinflammatory and antinociceptive effects of the selective histamine H4-receptor antagonists JNJ7777120 and VUF6002 in a rat model of carrageenan-induced acute inflammation. Eur. J. Pharmacol. 2007; 563 (1–3): 240–4. DOI: 10.1016/j.ejphar.2007.02.026
Zhang H., Han G.W., Batyuk A. et al. Structural basis of ligand recognition at the human MT1 melatonin receptor. Nature. 2019; 573 (7772): 55–9. DOI: 10.1038/s41586-019-1520-9
Adachi T., Aoki Y., Yoshida H. et al. Reduction of Mg2+ block of synaptic NMDA receptors in developing rat substantia nigra dopaminergic neurons. J. Physiol. 2010; 588 (Pt 21): 4221–37. DOI: 10.1113/jphysiol.2010.193334
Sadek B., Khanian S.S., Ashoor A. et al. Effects of antihistamines on the function of human α7-nicotinic acetylcholine receptors. Eur. J. Pharmacol. 2015; 746: 308–16. DOI: 10.1016/j.ejphar.2014.10.046
Feng Z., Hou T., Li Y. Docking and MD study of histamine H4R based on the crystal structure of H1R. J. Mol. Graph Model. 2013; 39: 1–12. doi: 10.1016/j.jmgm.2012.11.001
Lucero M.L., Gonzalo A., Ganza A. et al. Interactions of bilastine, a new oral H1 antihistamine, with human transporter systems. Drug Chem Toxicol. 2012; 35 (Suppl 1): 8–17. doi: 10.3109/01480545.2012.682660
Ji-Hun Jang, Seung-Hyun Jeong, Yong-Bok Lee. Quantitative assessment of the relevance of organic-anion-transporting-polypeptide 1B1 and 2B1 polymorphisms in fexofenadine pharmacokinetic variants via pharmacometrics[J]. J. of Pharmaceutical Analysis. 2023; 13 (6): 660–72. DOI: 10.1016/j.jpha.2023.04.001
Batool M., Zamir A., Alqahtani F., et al. Clinical Pharmacokinetics of Fexofenadine: A Systematic Review. Pharmaceutics. 2024; 16 (12): 1619. DOI: 10.3390/pharmaceutics16121619