Background: Lidocaine has cardiovascular and neurologic toxicity, which is dosedependent. Due to CYP3A4-involved metabolism, lidocaine may be prone to drug-drug interactions. Materials and Methods: Given statins have the possibility of combination with lidocaine in the clinic, we established in vitro models to assess the effect of statins on the metabolism of lidocaine. Further pharmacokinetic alterations of lidocaine and its main metabolite, monoethylglycinexylidide in rats influenced by simvastatin, were investigated. Results: In vitro study revealed that simvastatin, among the statins, had the most significant inhibitory effect on lidocaine metabolism with IC 50 of 39.31 µM, 50 µM and 15.77 µM for RLM, HLM and CYP3A4.1, respectively. Consistent with in vitro results, lidocaine concomitantly used with simvastatin in rats was associated with 1.2-fold AUC (0-t) , 1.2-fold AUC (0-∞) , and 20%-decreased clearance for lidocaine, and 1.4-fold C max for MEGX compared with lidocaine alone. Conclusion: Collectively, these results implied that simvastatin could evidently inhibit the metabolism of lidocaine both in vivo and in vitro. Accordingly, more attention and necessary therapeutic drug monitoring should be paid to patients with the concomitant coadministration of lidocaine and simvastatin so as to avoid unexpected toxicity.