Gliflozins are a class of drugs used to treat type 2 diabetes in humans but have also been investigated for treatment of insulin dysregulation to lower hyperinsulinemia and prevent laminitis in horses. They act by inhibiting sodium/glucose cotransporter protein 2 (SGLT2), resulting in increased urinary glucose excretion and lower glucose levels in blood, but they can also provide cardiovascular benefits and could therefore potentially be used as performance enhancers in sports. Currently, only the plasma pharmacokinetics of one SGLT2 inhibitor, canagliflozin, have been reported in horses, and there is no published information about metabolism and detection of gliflozins in horses. Therefore, the aim of this study was to gain a better understanding of the metabolism of ertugliflozin in the equine following a multidose oral administration of Steglatro® (0.05 mg/kg once a day for 5 days) to two Thoroughbred horses.
Initially, unhydrolysed and hydrolysed plasma and urine samples were analysed by LC-HRMS to identify any potential phase I and II metabolites. O-desethylated ertugliflozin was identified as a minor metabolite in both matrices. The metabolite was predominantly glucuronide conjugated, meanwhile, the parent compound was mainly present unconjugated. Subsequently, target LC-MS/MS methods were developed for semi-quantitative analysis of ertugliflozin in plasma (0.1 – 250 ng/mL) and urine (0.5 – 250 ng/mL) to assess detection of ertugliflozin in these matrices following administration. Ertugliflozin was detected with peak concentrations of 27.6 and 29.0 ng/mL in plasma and 86.2 and 91.7 ng/mL in urine from two horses. Ertugliflozin was detected for 14 days post-administration in the plasma of both horses; meanwhile, its detection was considerably shorter in urine, at 5 and 6 days post-administration.