The long duration of action of the second generation antihistamine bilastine coincides with its long residence time at the histamine H1 receptor

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Abstract

Drug-target binding kinetics has recently attracted considerable interest in view of the potential predictive power for in vivo drug efficacy. The recently introduced antihistamine bilastine has a long duration of in vivo drug action, which outlasts pharmacological active bilastine concentrations in blood. To provide a molecular basis for the long duration of action, we explored the kinetics of bilastine binding to the human histamine H1 receptor using [3H]mepyramine binding studies and compared its pharmacodynamics properties to the reference compounds fexofenadine and diphenhydramine, which have a long (60 ± 20 min) and short (0.41 ± 0.1 min) residence time, respectively. Bilastine shows a long drug-target residence time at the H1 receptor (73 ± 5 min) and this results in a prolonged H1 receptor antagonism in vitro (Ca2+ mobilization in Fluo-4 loaded HeLa cells), following a washout of unbound antagonist. Hence, the long residence time of bilastine can explain the observed long duration of drug action in vivo.

Original languageEnglish
Pages (from-to)107-111
Number of pages5
JournalEuropean Journal of Pharmacology
Volume838
Early online date7 Sep 2018
DOIs
Publication statusPublished - 5 Nov 2018

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Non-Sedating Histamine H1 Antagonists
Histamine H1 Receptors
fexofenadine
Pharmaceutical Preparations
Pyrilamine
Diphenhydramine
Histamine Antagonists
HeLa Cells
bilastine
Pharmacology

Keywords

  • Antagonism
  • Bilastine
  • Dissociation rate constant
  • Duration of action
  • Histamine H receptor
  • Residence time

Cite this

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title = "The long duration of action of the second generation antihistamine bilastine coincides with its long residence time at the histamine H1 receptor",
abstract = "Drug-target binding kinetics has recently attracted considerable interest in view of the potential predictive power for in vivo drug efficacy. The recently introduced antihistamine bilastine has a long duration of in vivo drug action, which outlasts pharmacological active bilastine concentrations in blood. To provide a molecular basis for the long duration of action, we explored the kinetics of bilastine binding to the human histamine H1 receptor using [3H]mepyramine binding studies and compared its pharmacodynamics properties to the reference compounds fexofenadine and diphenhydramine, which have a long (60 ± 20 min) and short (0.41 ± 0.1 min) residence time, respectively. Bilastine shows a long drug-target residence time at the H1 receptor (73 ± 5 min) and this results in a prolonged H1 receptor antagonism in vitro (Ca2+ mobilization in Fluo-4 loaded HeLa cells), following a washout of unbound antagonist. Hence, the long residence time of bilastine can explain the observed long duration of drug action in vivo.",
keywords = "Antagonism, Bilastine, Dissociation rate constant, Duration of action, Histamine H receptor, Residence time",
author = "Reggie Bosma and {van den Bor}, Jelle and Vischer, {Henry F.} and Luis Labeaga and Rob Leurs",
year = "2018",
month = "11",
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T1 - The long duration of action of the second generation antihistamine bilastine coincides with its long residence time at the histamine H1 receptor

AU - Bosma, Reggie

AU - van den Bor, Jelle

AU - Vischer, Henry F.

AU - Labeaga, Luis

AU - Leurs, Rob

PY - 2018/11/5

Y1 - 2018/11/5

N2 - Drug-target binding kinetics has recently attracted considerable interest in view of the potential predictive power for in vivo drug efficacy. The recently introduced antihistamine bilastine has a long duration of in vivo drug action, which outlasts pharmacological active bilastine concentrations in blood. To provide a molecular basis for the long duration of action, we explored the kinetics of bilastine binding to the human histamine H1 receptor using [3H]mepyramine binding studies and compared its pharmacodynamics properties to the reference compounds fexofenadine and diphenhydramine, which have a long (60 ± 20 min) and short (0.41 ± 0.1 min) residence time, respectively. Bilastine shows a long drug-target residence time at the H1 receptor (73 ± 5 min) and this results in a prolonged H1 receptor antagonism in vitro (Ca2+ mobilization in Fluo-4 loaded HeLa cells), following a washout of unbound antagonist. Hence, the long residence time of bilastine can explain the observed long duration of drug action in vivo.

AB - Drug-target binding kinetics has recently attracted considerable interest in view of the potential predictive power for in vivo drug efficacy. The recently introduced antihistamine bilastine has a long duration of in vivo drug action, which outlasts pharmacological active bilastine concentrations in blood. To provide a molecular basis for the long duration of action, we explored the kinetics of bilastine binding to the human histamine H1 receptor using [3H]mepyramine binding studies and compared its pharmacodynamics properties to the reference compounds fexofenadine and diphenhydramine, which have a long (60 ± 20 min) and short (0.41 ± 0.1 min) residence time, respectively. Bilastine shows a long drug-target residence time at the H1 receptor (73 ± 5 min) and this results in a prolonged H1 receptor antagonism in vitro (Ca2+ mobilization in Fluo-4 loaded HeLa cells), following a washout of unbound antagonist. Hence, the long residence time of bilastine can explain the observed long duration of drug action in vivo.

KW - Antagonism

KW - Bilastine

KW - Dissociation rate constant

KW - Duration of action

KW - Histamine H receptor

KW - Residence time

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