The shortcoming of using glibenclamide in exploratory clinical headache provocation studies.

Objective: Preclinical and clinical studies implicate the vascular ATP-sensitive potassium (K_ATP) channel in the signaling cascades underlying headache and migraine. However, attempts to demonstrate that the K_ATP 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 K_ATP 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 K_ATP 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 K_ATP channel inhibition in the treatment of migraine.