Key result
Higher drug lipophilicity correlates strongly with potent KATP channel blockade, accurately predicting simvastatin inhibition.
Why the study?
Does drug lipophilicity (logP) predict the potency of nonsulphonylurea drugs and statins (simvastatin and pravastatin) to block pancreatic beta-cell KATP channels and stimulate insulin secretion?
Does drug lipophilicity (logP) predict the potency of nonsulphonylurea drugs and statins (simvastatin and pravastatin) to block pancreatic beta-cell KATP channels and stimulate insulin secretion?
Although lipophilicity accurately predicts that simvastatin potently blocks pancreatic beta-cell KATP channels in vitro, high serum protein binding and lower therapeutic plasma concentrations prevent acute statin-induced insulin secretion and clinical hypoglycaemia.
Answers are grounded in this paper and cite their sources.
Serum binding precludes acute insulin secretion despite in vitro KATP blockade; leaves open relevance of lipophilicity models to clinical statin effects.
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.
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Real et al. (2018) studied Pancreatic beta-cell KATP channel blockade and insulin secretion (n=26). Simvastatin and pravastatin (plus 26 lipophilic nonsulphonylurea drugs) vs. Vehicle controls (0.1% vol/vol DMSO, ethanol, or H2O) and tolbutamide (20 μmol/L) was evaluated on Correlation between drug lipophilicity (logP) and potency (Log IC50) for pancreatic beta-cell KATP channel block, and experimental IC50 of simvastatin (r = -0.81; Simvastatin IC50 26 nmol/L (inside-out) and 31 nmol/L (whole-cell), 95% CI 18-37 nmol/L (inside-out); 20-42 nmol/L (whole-cell), p=<0.001). Drug lipophilicity (logP) linearly predicted KATP channel block potency (r = -0.81, P < 0.001), accurately forecasting simvastatin blockade (IC50 26 nmol/L), though serum binding prevented insulin release.
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