Hepatic microsomal cytochrome P450 (CYP) isozymes are important for the in vitro and in vivo metabolism of tofacitinib in rats. However, the study that which types of CYP isozymes are related have not been reported yet. In this study, in vitro to confirm that tofacitinib is metabolized by specific CYP. Furthermore, we conducted inhibitor kinetics experiments with specific inhibitors (ketoconazole, fluconazole, fluvoxamine). Vmax is the same, and Km value is different, it can be confirmed that it is a competitive inhibitor. In order to prove the in vitro we further proceeded with the in vivo experiment. Tofacitinib at a dose of 10 mg/kg was intravenously administered to rats pretreated with various inducers of CYP isozymes, such as dexamethasone, rifampicin, omeprazole and orphenadrine (the main inducers of CYP3A4, 2C9/19, 1A1/2, 2B1/2) and inhibitors, such as SKF 525A (a non-specific of inhibitor of CYP isozymes), ketoconazole, fluconazole, fluvoxamine and quinidine (the main inhibitors of CYP3A4, 2C19, 2C9 and 2D6). In rats pretreated with dexamethasone phosphate and rifampicin, the time-averaged nonrenal clearance (CLNR) was outstandingly faster (232 and 49.2% increase) than those in control rats. In rats pretreated with ketoconazole and fluconazole, the CLNR was outstandingly slower (45.4 and 38.7% decrease) than those in control rats. Taken together, the results suggest that tofacitinib is predominantly metabolized via the CYP3A4 and 2C19 in rats.
