Binding of sulphonylureas to plasma proteins - A KATP channel perspective.

Article Details


Proks P, Kramer H, Haythorne E, Ashcroft FM

Binding of sulphonylureas to plasma proteins - A KATP channel perspective.

PLoS One. 2018 May 17;13(5):e0197634. doi: 10.1371/journal.pone.0197634. eCollection 2018.

PubMed ID
29772022 [ View in PubMed

Sulphonylurea drugs stimulate insulin secretion from pancreatic beta-cells primarily by inhibiting ATP sensitive potassium (KATP) channels in the beta-cell membrane. The effective sulphonylurea concentration at its site of action is significantly attenuated by binding to serum albumin, which makes it difficult to compare in vitro and in vivo data. We therefore measured the ability of gliclazide and glibenclamide to inhibit KATP channels and stimulate insulin secretion in the presence of serum albumin. We used this data, together with estimates of free drug concentrations from binding studies, to predict the extent of sulphonylurea inhibition of KATP channels at therapeutic concentrations in vivo. KATP currents from mouse pancreatic beta-cells and Xenopus oocytes were measured using the patch-clamp technique. Gliclazide and glibenclamide binding to human plasma were determined in spiked plasma samples using an ultrafiltration-mass spectrometry approach. Bovine serum albumin (60g/l) produced a mild, non-significant reduction of gliclazide block of KATP currents in pancreatic beta-cells and Xenopus oocytes. In contrast, glibenclamide inhibition of recombinant KATP channels was dramatically suppressed by albumin (predicted free drug concentration <0.1%). Insulin secretion was also reduced. Free concentrations of gliclazide and glibenclamide in the presence of human plasma measured in binding experiments were 15% and 0.05%, respectively. Our data suggest the free concentration of glibenclamide in plasma is too low to account for the drug's therapeutic effect. In contrast, the free gliclazide concentration in plasma is high enough to close KATP channels and stimulate insulin secretion.

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