Pharmacodynamic and pharmacokinetic interactions between simvastatin and diazepam in rats

Background: Statins and benzodiazepines are widely used drugs, especially in ischemic heart disease, where exacerbation caused by anxiety can even lead to cardiac death. There have not been any reports of statin drug interaction with anxiolytics so far, but it is possible that these drugs interact with each other. We examined the effect of chronic oral administration of simvastatin on the anxiolytic activity and pharmacokinetics of diazepam in rats. Methods: Studies were conducted on male Wistar Han rats treated with simvastatin (2.5, 5, 10, 20 mg/kg) for 4-6 weeks, and/or diazepam (2.5, 5, 10 mg/kg) administered once on the day of the study. Evaluation of potential pharmacodynamic interaction was based on the behavioral tests: elevated plus maze (EPM) test and the Vogel conflict test (VCT). The assessment of the potential pharmacokinetic interaction was based on measurements of concentrations of diazepam and its metabolites in the blood of animals. Results: Diazepam 5 and 10 mg/kg given together with simvastatin 10 and 20 mg/kg showed no anxiolytic effect in the EPM test. In the VCT diazepam combinations with simvastatin did not produce any anxiolytic effect either, with an exception of the co-administration of diazepam 10 mg/kg and simvastatin 10 mg/kg. Simvastatin (20 mg/kg) significantly reduced the area under curve (AUC) of diazepam by 51.6% and temazepam by 54.6%. Conclusions: Abolition of diazepam anxiolytic effect during concomitant use of simvastatin is probably caused by diminished bioavailability of diazepam, although pharmacodynamic interaction between these drugs cannot be excluded. (c) 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.