Co-administration with simvastatin or lovastatin alters the pharmacokinetic profile of sinomenine in rats through cytochrome P450-mediated pathways

Sinomenine, an anti-rheumatoid arthritis drug used in China for decades, is usually co-administered with cardiovascular (CV) drugs to reduce arthritis-related risk of cardiovascular diseases. This study was to investigate whether and how CV drugs affect the pharmacokinetic profile of sinomenine. In rat liver microsomes (RLMs), the key metabolic enzymes of sinomenine were identified by using specific inhibitors. The influences of CV drugs, including propranolol, verapamil, warfarin, atorvastatin, simvastatin, and lovastatin, on the metabolism of sinomenine were examined. Cocktail probe, RT-qPCR, and western blotting were performed to unveil the underlying mechanism of the drug-drug interaction. The key metabolic enzymes of sinomenine were identified to be CYP3A1/2 and CYP2D1 in RLMs. Among the CV drugs screened, simvastatin and lovastatin were shown to inhibit the liver metabolism of sinomenine with Ki values of 13.00 and 25.83 μM, respectively. Single administration of simvastatin or lovastatin in rats increased the AUC value of sinomenine to 1.40- or 1.50-fold, and decreased the CLz/F value to 68.19% or 65.44%, respectively. In contrast, multiple administrations of simvastatin, but not lovastatin, increased the CLz/F value of sinomenine to 1.38-fold and decreased the AUC value to 71.59%. Further studies showed that the long-term administration of simvastatin could up-regulate the expression of CYP3A1/2 to account for the effect. This study demonstrated the potential effect of simvastatin and lovastatin on the metabolism of sinomenine for the first time. The findings provide guidelines for the co-administration of sinomenine with simvastatin or lovastatin in clinic.