Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
Clinical Research Department, Faes Farma SA, Leioa, Bizkaia, Spain.
Eur J Pharmacol. 2018 Nov 5;838:107-111. doi: 10.1016/j.ejphar.2018.09.011. Epub 2018 Sep 7.
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 H receptor using [H]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 H receptor (73 ± 5 min) and this results in a prolonged H receptor antagonism in vitro (Ca 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.
鉴于药物 - 靶标结合动力学在预测体内药物疗效方面具有潜在的预测能力，因此最近引起了广泛关注。最近推出的抗组胺药比拉斯汀具有较长的体内药物作用持续时间，超过了血液中具有药理活性的比拉斯汀浓度。为了提供长效作用的分子基础，我们使用 [H] 美吡拉敏结合研究探索了比拉斯汀与人组胺 H 受体结合的动力学，并将其药效学特性与具有长（60 ± 20 分钟）和短（0.41 ± 0.1 分钟）居留时间的参考化合物非索非那定和苯海拉明进行了比较。比拉斯汀在 H 受体上显示出较长的药物 - 靶标居留时间（73 ± 5 分钟），这导致体外 H 受体拮抗作用延长（用 Fluo-4 加载的 HeLa 细胞中的钙动员），在洗脱未结合的拮抗剂后。因此，比拉斯汀的长居留时间可以解释体内观察到的药物作用持续时间长的原因。
