In vitro profiling of the metabolism and drug–drug interaction of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, using human liver microsomes, human hepatocytes, and recombinant human CYP

Abstract1. The metabolism and drug–drug interaction(DDI) risk of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, were evaluated by in vitro studies using human livermicrosomes, human hepatocytes, and recombinant human CYPs.2. The main metabolite of tofogliflozinwas the carboxylated derivative (M1) in human hepatocytes, which was the same as in vivo. The metabolic pathway of tofogliflozinto M1 was considered to be as follows: first, tofogliflozinwas catalyzed to the primary hydroxylated derivative (M4) by CYP2C18, CYP4A11and CYP4F3B, then M4 was oxidized to M1.3. Tofogliflozinhad no induction potential on CYP1A2and CYP3A4. Neither tofogliflozinnor M1 had inhibition potential on CYPs, with the exception of a weak CYP2C19inhibition by M1.4. Not only are multiple metabolic enzymes involved in the tofogliflozinmetabolism, but the drug is also excreted into urine after oral administration, indicating that tofogliflozinis eliminated through multiple pathways. Th...