Lipophilicity predicts the ability of nonsulphonylurea drugs to block pancreatic beta‐cell KATP channels and stimulate insulin secretion; statins as a test case

摘要

Aims: KATP ion channels play a key role in glucose-stimulatedinsulin secretion.However, many drugs block KATP as “off targets” leading to hyperinsulinaemia andhypoglycaemia. As such drugs are often lipophilic, the aim was to examine the relationshipbetween drug lipophilicity (P) and IC50 for KATP block and explore if the IC50’sof statins could be predicted from their lipophilicity and whether this would allowone to forecast their acute action on insulin secretion.Materials and methods: A meta-analysisof 26 lipophilic, nonsulphonylurea, blockersof KATP was performed. From this, the IC50’s for pravastatin and simvastatin werepredicted and then tested experimentally by exploring their effects on KATP channelactivity via patch-clampmeasurement, calcium imaging and insulin secretion in murinebeta cells and islets.Results: Nonsulphonylurea drugs inhibited KATP channels with a Log IC50 linearly relatedto their logP. Simvastatin blocked KATP with an IC50 of 25 nmol/L, a value independentof cytosolic factors, and within the range predicted by its lipophilicity(21-690nmol/L). 10 μmol/L pravastatin, predicted IC50 0.2-12mmol/L, was withouteffect on the KATP channel. At 10-foldtherapeutic levels, 100 nmol/L simvastatindepolarized the beta-cellmembrane potential and stimulated Ca2+ influx but did notaffect insulin secretion; the latter could be explained by serum binding.Conclusions: The logP of a drug can aid prediction for its ability to block beta-cellKATP ion channels. However, although the IC50 for the block of KATP by simvastatinwas predicted, the difference between this and therapeutic levels, as well as serumsequestration, explains why hypoglycaemia is unlikely to be observed with acute useof this statin.