Effects of CYP2D6 and CYP2C19 genetic polymorphisms and cigarette smoking on the pharmacokinetics of tolperisone

Tolperisone, a muscle relaxant used for post-stroke spasticity, is metabolized to its main metabolite by CYP2D6 and to a lesser extent by CYP2C19 and CYP1A2. We investigated the effects of CYP2D6 and CYP2C19 genetic polymorphisms and cigarette smoking on tolperisone pharmacokinetics. A 150 mg oral dose of tolperisone was given to 184 healthy Korean subjects and plasma concentrations of tolperisone were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). A 3.14-fold significant increase in AUC(0-infinity) was observed in the CYP2D6*10/*10 group compared with the CYP2D6*wt/*wt group, whereas a 3.59-fold increase in AUC(0-infinity) was observed in CYP2C19PMs compared to CYP2C19EMs. Smokers had a 38.5% decrease in AUC(0-infinity) when compared to non-smokers. When these effects were combined, CYP2D6*10/*10-CYP2C19PM-Non-smokers had a 25.9-fold increase in AUC(0-infinity) compared to CYP2D6*wt/*wt-CYP2C19EM-Smokers. Genetic polymorphisms of CYP2D6 and CYP2C19 and cigarette smoking independently and significantly affected tolperisone pharmacokinetics and these effects combined resulted in a much greater impact on tolperisone pharmacokinetics.

Automated summary

This study investigated the impact of genetic polymorphisms of CYP2D6 and CYP2C19, as well as cigarette smoking, on the pharmacokinetics of tolperisone. The results showed that these factors independently affected tolperisone metabolism, and their combined effects had a greater impact.