Effects of CYP۲C۱۹ variants on the metabolism of tapentadol in vitro

Objective(s): This study aims to evaluate the catalytic activities of ۳۱ CYP۲C۱۹ alleles and their effects on the metabolism of tapentadol in vitro. Materials and Methods: Insect microsomes expressing the CYP۲C۱۹ alleles were incubated with ۵۰–۱۲۵۰ μM tapentadol for ۴۰ min at ۳۷ °C and terminated by cooling to -۸۰ °C, immediately. Tapentadol and N-desmethyl tapentadol were analyzed by a UPLC-MS/MS system. The kinetic parameters Km, Vmax, and intrinsic clearance (Vmax/Km) of N-desmethyl tapentadol were determined. Results: As a result, the intrinsic clearance (Vmax/Km) values of most variants were significantly altered, while CYP۲C۱۹.۳ and ۳۵FS had no detectable enzyme activity. Only one variant, N۲۷۷K, showed no significant difference from CYP۲C۱۹.۱B. Two variants CYP۲C۱۹.۲۹ and L۱۶F displayed markedly increased intrinsic clearance values of ۳۰۲.۲۲% and ۱۹۹.۹۷%, respectively; whereas ۲۴ variants exhibited significantly decreased relative clearance ranging from ۰.۳۲% to ۷۹.۱۵% of CYP۲C۱۹.۱B. Especially, CYP۲C۱۹.۲G, ۲H, R۱۲۴Q, and R۲۶۱W exhibited a drastic decrease in clearance (>۸۰%) compared with wild-type CYP۲C۱۹.۱B. Conclusion: As the first study of all aforementioned alleles for tapentadol metabolism, the comprehensive data in vitro may provide novel insights into the allele-specific and substrate-specific activity of CYP۲C۱۹.

Keywords:

Cytochrome P۴۵۰ , CYP۲C۱۹ variants , Drug metabolism , Genetic polymorphism , Tapentadol