Biotransformation and mass balance of the SGLT2 inhibitor empagliflozin in healthy volunteers

Abstract

1. The absorption, biotransformation and excretion of empagliflozin, an SGLT2 inhibitor, were evaluated in eight healthy subjects following a single 50 mg oral dose of empagliflozin containing ∼100 µCi [¹⁴C]-empagliflozin.

2. Radioactivity was rapidly absorbed, with plasma levels peaking 1 h post-dose. Total exposure was lower in blood versus plasma, consistent with moderate (28.6–36.8%) red blood cell partitioning. Protein binding was 80.3–86.2%.

3. Most of the radioactive dose was recovered in urine (54.4%) and faeces (41.1%). Unchanged empagliflozin was the most abundant drug-related component in plasma, representing 75.5–77.4% of plasma radioactivity and 79.6% plasma radioactivity AUC_0–12 h. Unchanged empagliflozin was the most abundant drug-related component in urine and faeces, representing 43.5% (23.7% of dose) and 82.9% (34.1% of dose) of radioactivity in urine and faeces, respectively. Six metabolites were identified in plasma: three glucuronide conjugates representing 4.7–7.1% of AUC_0–12 h and three less abundant metabolites (<0.2–1.9% AUC_0–12 h). The most abundant metabolites in urine were two glucuronide conjugates (7.8–13.2% of dose) and in faeces was a tetrahydrofuran ring-opened carboxylic acid metabolite (1.9% of dose).

4. To conclude, empagliflozin was rapidly absorbed and excreted primarily unchanged in urine and faeces. Unchanged parent was the major drug-related component in plasma. Metabolism was primarily via glucuronide conjugation.

• Absorption
• excretion
• metabolic pathway
• metabolite
• pharmacokinetics
• radiolabeled

Acknowledgements

The authors acknowledge the contribution of Debra Mandarino, MD, who was the principal investigator at the clinical site (Covance Laboratories, Madison, WI).

Declaration of interest

Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Clare Ryles and Wendy Morris of Fleishman-Hillard Group, Ltd, during the preparation of this article. This study was funded by Boehringer Ingelheim. All authors are employees of Boehringer Ingelheim. The authors were fully responsible for all content and editorial decisions and were involved at all stages of article development and have approved the final version.