Metabolism and mass balance of SGLT2 inhibitor tofogliflozin following oral administration to humans

Abstract

1. Tofogliflozin is a novel and selective SGLT2 inhibitor increasing glucosuria by inhibition of glucose re-absorption in the kidney for the treatment of type 2 diabetes mellitus. 2. In this study, the metabolism and the mass balance of tofogliflozin was evaluated following administration of a single oral dose of 20 mg [(14)C]-tofogliflozin to six healthy subjects. 3. Tofogliflozin underwent mainly oxidative metabolism in the ethylphenyl moiety, but also minor glucuronide conjugates of metabolites and the parent drug were formed. 4. In plasma, the parent drug and its major phenyl acetic acid metabolite M1 accounted for 42% and 52% of the total drug-related material, respectively. The hydroxyl metabolites and their successor ketone metabolite showed an exposure well below 5%, along with an acyl glucuronide of M1. 5. Tofogliflozin was completely absorbed with subsequent predominate metabolic clearance and a small contribution of direct urinary elimination. Approximately, 76% of the dose was excreted in urine and 20% in faeces within 72 h. The high absorption of tofogliflozin was exemplified by the small trace of parent drug in faeces. The phenyl acetic acid metabolite M1 was the major component excreted in urine and faeces accounting for more than half of the dose. Tofogliflozin demonstrated a high metabolic turnover.

In vitroprofiling 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

“…14 C]tofogliflozin to healthy subjects was 1814, 2215, 225, and 136 ng h/mL for tofogliflozin, M1, M2/ M3, and M5, respectively, and that M1 was found to be the major metabolite in urine and feces (Zell et al, 2013). These results suggested that the main metabolite of tofogliflozin was M1 in human.…”

“…M2/M3 and M5 are also considered not to affect the in vivo efficacy: the AUC 0-24h values of M2/M3 and M5 were 225 and 136 ng h/ mL, respectively (Zell et al, 2013), and in vivo potency of M2/M3 and M5 versus tofogliflozin was estimated to be 0.2 and 0.1, respectively, even when their f p was 1. Because the exposure of M4 was undetectable (Zell et al, 2013), it was considered that it would not influence in vivo efficacy.…”

“…In vivo inhibition potency of metabolite versus tofogliflozin ¼ AUC of unbound metabolite=IC 50 of metabolite AUC of unbound tofogliflozin=IC 50 of tofogliflozin Considering that the f p of tofogliflozin and M1 in human plasma were 0.17 (Schwab et al, 2013) and 0.45 (at 0.1 mg/ mL because of its C max , Table 6), respectively, and their AUC 0-24h values were 1814 and 2215 ng h/mL, respectively (Zell et al, 2013), it was expected that M1 would not show additional efficacy, because in vivo inhibition potency of M1 versus tofogliflozin was estimated to be 0.005. M2/M3 and M5 are also considered not to affect the in vivo efficacy: the AUC 0-24h values of M2/M3 and M5 were 225 and 136 ng h/ mL, respectively (Zell et al, 2013), and in vivo potency of M2/M3 and M5 versus tofogliflozin was estimated to be 0.2 and 0.1, respectively, even when their f p was 1.…”

In vitro evaluation of potential drug interactions mediated by cytochrome P450 and transporters for luseogliflozin, an SGLT2 inhibitor

“…The urinary excretion of tofogliflozin and empagliflozin in humans has been reported to be $20% of the dose (Macha et al, 2014;Zell et al, 2014). Because the urinary excretion is greater than the glomerular filtrated amount, estimated from the plasma unbound AUC of the drug, these drugs are thought to be secreted in the renal tubules.…”

Effects of Child-Pugh B Cirrhosis on Pharmacokinetics of Tofogliflozin, a New Sodium-Glucose Co-Transporter (SGLT2) Inhibitor

“…An in vitro study has shown that tofogliflozin is metabolized by enzymes CYP2C18, 3A4/5, 4A11, and 4F3B [11]. Mass balance studies have shown that tofogliflozin in systemic circulation is eliminated mainly by metabolism, and a major part (75.5 % of the dose) of tofogliflozin and its metabolites is eliminated by urinary excretion [9,12].…”