Abstract
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.