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

Arch Pharm Res. 2023 Aug;46(8):713-721. doi: 10.1007/s12272-023-01462-1. Epub 2023 Sep 20.

Abstract

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 AUC0-∞ was observed in the CYP2D6*10/*10 group compared with the CYP2D6*wt/*wt group, whereas a 3.59-fold increase in AUC0-∞ was observed in CYP2C19PMs compared to CYP2C19EMs. Smokers had a 38.5% decrease in AUC0-∞ when compared to non-smokers. When these effects were combined, CYP2D6*10/*10-CYP2C19PM-Non-smokers had a 25.9-fold increase in AUC0-∞ 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.

Keywords: CYP1A2; CYP2C19; CYP2D6; Genetic polymorphism; Pharmacokinetics; Smoking; Tolperisone.

MeSH terms

  • Area Under Curve
  • Chromatography, Liquid
  • Cigarette Smoking*
  • Cytochrome P-450 CYP2C19 / genetics
  • Cytochrome P-450 CYP2C19 / metabolism
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 CYP2D6 / metabolism
  • Genotype
  • Humans
  • Polymorphism, Genetic
  • Tandem Mass Spectrometry
  • Tolperisone* / pharmacokinetics

Substances

  • Cytochrome P-450 CYP2D6
  • Tolperisone
  • Cytochrome P-450 CYP2C19
  • CYP2C19 protein, human