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

Summary Aims K ATP ion channels play a key role in glucose‐stimulated insulin secretion. However, many drugs block K ATP as “off targets” leading to hyperinsulinaemia and hypoglycaemia. As such drugs are often lipophilic, the aim was to examine the relationship between drug lipophilicity (P) and IC 50 for K ATP block and explore if the IC 50 's of statins could be predicted from their lipophilicity and whether this would allow one to forecast their acute action on insulin secretion. Materials and methods A meta‐analysis of 26 lipophilic, nonsulphonylurea, blockers of K ATP was performed. From this, the IC 50 's for pravastatin and simvastatin were predicted and then tested experimentally by exploring their effects on K ATP channel activity via patch‐clamp measurement, calcium imaging and insulin secretion in murine beta cells and islets. Results Nonsulphonylurea drugs inhibited K ATP channels with a Log IC 50 linearly related to their logP. Simvastatin blocked K ATP with an IC 50 of 25 nmol/L, a value independent of cytosolic factors, and within the range predicted by its lipophilicity (21‐690 nmol/L). 10 μmol/L pravastatin, predicted IC 50 0.2‐12 mmol/L, was without effect on the K ATP channel. At 10‐fold therapeutic levels, 100 nmol/L simvastatin depolarized the beta‐cell membrane potential and stimulated Ca 2+ influx but did not affect 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‐cell K ATP ion channels. However, although the IC 50 for the block of K ATP by simvastatin was predicted, the difference between this and therapeutic levels, as well as serum sequestration, explains why hypoglycaemia is unlikely to be observed with acute use of this statin.