Lipophilicity predicts the ability of nonsulphonylurea drugs to block pancreatic beta-cell KATP channels and stimulate insulin secretion; statins as a test case.
Aims
KATP ion channels play a key role in glucose-stimulated insulin secretion. However, many drugs block KATP 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 KATP 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 KATP was performed. From this, the IC 50's for pravastatin and simvastatin were predicted and then tested experimentally by exploring their effects on KATP channel activity via patch-clamp measurement, calcium imaging and insulin secretion in murine beta cells and islets.


Results
Nonsulphonylurea drugs inhibited KATP channels with a Log IC 50 linearly related to their logP. Simvastatin blocked KATP 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 KATP channel. At 10-fold therapeutic levels, 100 nmol/L simvastatin depolarized the beta-cell membrane potential and stimulated Ca2+ 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 KATP ion channels. However, although the IC 50 for the block of KATP 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.
['Real|Joana|J|', 'Miranda|Caroline|C|', 'Olofsson|Charlotta S|CS|', 'Smith|Paul A|PA|0000-0002-8710-6830']
KATP channel insulin simvastatin beta‐cell