Better SGLT2 Inhibitor Analysis

Scientists in Japan have found a new, highly sensitive technique called liquid chromatography-tandem mass spectrometry (LC-MS/MS) that could improve analysis of new SGLT2 inhibitors.

The study tested ipragliflozin in rats using the LC-MS/MS technique. Results showed that pharmacokinetics of ipragliflozin in rats are similar to those in humans.

Ipragliflozin is a highly potent inhibitor of the SGLT2 receptor, resulting in decreased reabsorption of glucose in the proximal tubule of the kidneys and increased urinary excretion of glucose. In 2014, ipragliflozin became the first SGLT2 inhibitor approved for the treatment of T2DM in Japan. The drug has yet to gain FDA approval in the US. Three SGLT2 inhibitors are currently FDA approved in the US:  dapagliflozin, canagliflozin, and empagliflozin.

SGLT2 inhibitors already on the market have been shown to decrease HbA1c and blood glucose levels. Use of SGLT2 inhibitors may result in mild to moderate decreases in body weight and blood pressure. Studies have suggested that SGLT2 may also prevent vascular complications of diabetes, as well as improve insulin sensitivity and pancreatic beta cell function.

Because SGLT2 inhibitors are such a new drug class, though, further pharmacodynamics and pharmacokinetic studies are needed. New laboratory techniques for assessing SGLT2 inhibitors could improve the quality of analysis.

In the study, researchers used empagliflozin as an internal standard, and performed liquid-liquid extraction and chromatographic separation to detect ipragliflozin in rat plasma. They also did a pharmacokinetic study in rats after oral administration of ipragliflozin.

Key Results

• Precision and accuracy of the LC-MS/MS method lay within FDA guidelines.

• Analyses validated the specificity and reproducibility of the LC-MS/MS method.

• Ipragliflozin was stable in rat plasma up to 24 hours at room temperature and upon refrigeration, and up to 10 days when stored at -80⁰ C.

• Pharmacokinetic studies showed similar results in rats as in humans:

♦ Maximal concentration: 349.8 ng/mL

♦ Time to maximal concentration: 1.2 hours

♦ Elimination half-life: 7.6 hours

♦ Volume of distribution: 4.4 L/kg

♦ Oral clearance: 4.4 L/kg

♦ Area under the curve (AUC): 2788.2 ng/mL

“These results suggest that the assay method is valuable for evaluating the pharmacokinetics of ipragliflozin in rats… This assay method may contribute to the assessment of novel SGLT2 inhibitors using rats as an animal model,” concluded lead author Toshiyuki Sakaeda, PhD, and colleagues at the Kyoto Pharmaceutical University in Kyoto, Japan.

Take-home Points

• The LC-MS/MS method is a new laboratory technique that could improve the assessment of new SGLT2 inhibitors in rats.

• Studies confirmed the precision, accuracy, specificity, and reproducibility of the LC-MS/MS method.

• Pharmacokinetic studies for ipragliflozin showed similar results in rats as in humans.

Reference: Kobuchi S, et al. A quantitative LC-MS/MS method for determining ipragliflozin, a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, and its application to a pharmacokinetic study in rats. J Chromatogr B Analyt Technol Biomed Life Sci. 2015 Sep 1;1000:22-28.