目的:临床前和临床研究提示血管ATP敏感性钾(KATP)通道参与了头痛和偏头痛的信号级联反应。然而,证明KATP通道抑制剂格列本脲可以减轻健康志愿者触发的头痛的尝试已证明不成功。这是值得怀疑的,然而,这些临床研究是否实现了目标参与.
方法:人类格列本脲药代动力学的文献数据,在已发表的探索性临床头痛激发研究中,使用血浆蛋白结合和功能IC50值预测格列本脲给药后获得的KATP受体占有率(RO)水平.ROvs.针对胰腺KATP通道亚型Kir6.2/SUR1和血管亚型Kir6.1/SUR2B模拟了格列本脲的时间曲线。
结果:在头痛激发研究中使用的10毫克格列本脲的临床剂量,Kir6.2/SUR1和Kir6.1/SUR2B的预测最大占用水平高达90%和高达26%,分别。
结论:本研究的结果表明,在使用格列本脲的临床头痛激发研究中,未实现有效的Kir6.1/SUR2B目标参与。因此,新型选择性Kir6.1/SUR2B抑制剂的开发,具有良好的生物利用度和低的血浆蛋白结合,需要揭示KATP通道抑制在偏头痛治疗中的潜力。
OBJECTIVE: Preclinical and clinical studies implicate the vascular ATP-sensitive potassium (
KATP) channel in the signaling cascades underlying headache and migraine. However, attempts to demonstrate that the
KATP channel inhibitor glibenclamide would attenuate triggered headache in healthy volunteers have proven unsuccessful. It is questionable, however, whether target engagement was achieved in these clinical studies.
METHODS: Literature data for human glibenclamide pharmacokinetics, plasma protein binding and functional IC50 values were used to predict the
KATP receptor occupancy (RO) levels obtained after glibenclamide dosing in the published exploratory clinical headache provocation studies. RO vs. time profiles of glibenclamide were simulated for the pancreatic
KATP channel subtype Kir6.2/SUR1 and the vascular subtype Kir6.1/SUR2B.
RESULTS: At the clinical dose of 10 mg of glibenclamide used in the headache provocation studies, predicted maximal occupancy levels of up to 90% and up to 26% were found for Kir6.2/SUR1 and Kir6.1/SUR2B, respectively.
CONCLUSIONS: The findings of the present study indicate that effective Kir6.1/SUR2B target engagement was not achieved in the clinical headache provocation studies using glibenclamide. Therefore, development of novel selective Kir6.1/SUR2B inhibitors, with good bioavailability and low plasma protein binding, is required to reveal the potential of
KATP channel inhibition in the treatment of migraine.