Effect of simvastatin on the metabolism and pharmacokinetics of felodipine in rats

Felodipine has been widely coadministered with simvastatin for the treatment of cardiovascular disease(CVD). However, in vitro and in vivo interactions between them have not been systemically understood. Herein, the effects of simvastatin on the in vitro metabolism and oral pharmacokinetic profile of felodipine were investigated. Felodipine was incubated in rat liver microsomes(RLMs)with or without simvastatin. Simvastatin was found to be a non-competitive inhibitor(inhibition constant(K_i): (9. 86±0. 27)μmol/L). Following oral combination of felodipine and simvastatin, the peak plasma concentration(c_max)and area under the plasma concentration-time curve(AUC_0-∞)of felodipine increased significantly, and the clearance(CL_z/F)decreased obviously, while the mean residence time(MRT_0-∞)and biological half-life(t1/2)were not statistically different. The altered pharmacokinetic profile of felodipine was probably due to the promoting effect of simvastatin on felodipine absorption. These findings provide some useful information for possible drug-drug interactions(DDIs)in rats, which should be paid particular attention to when felodipine and simvastatin are coadministered in clinical.