Abstract
Canagliflozin is a novel, orally selective inhibitor of sodium-dependent glucose co-transporter-2 (SGLT2) for the treatment of patients with type 2 diabetes mellitus. In this study, a sensitive and efficient UPLC-MS/MS method for the quantification of canagliflozin and its metabolites in rat plasma was established and applied to pharmacokinetics in a type 2 diabetic rat model. We firstly investigated the pharmacokinetic changes of canagliflozin and its metabolites in type 2 diabetic rats in order to use canagliflozin more safely, reasonably and effectively. We identified three types of O-glucuronide metabolites (M5, M7 and M17), two kinds of oxidation metabolites (M8 and M9) and one oxidation and glucuronide metabolite (M16) using API 5600 triple-TOF-MS/MS. Following liquid–liquid extraction by tert-butyl methyl ether, chromatographic separation of canagliflozin and its metabolites were performed on a Waters XBridge BEH C18 column (100 × 2.1 mm, 2.5 μm) using 0.1% acetonitrile–formic acid (75:15, v/v) as the mobile phase at a flow rate of 0.7 mL/min. Selected ion monitoring transitions of m/z 462.00→191.10, 451.20→153.10, 638.10→191.10 and 478.00→267.00 were chosen to quantify canagliflozin, empagliflozin (IS), O-glucuronide metabolites (M5, M7 and M17), and oxidation metabolites (M9) using an API 5500-triple-MS/MS in the positive electrospray ionization mode. The validation of the method was found to be of sufficient specificity, accuracy and precision. The pathological condition of diabetes could result in altered pharmacokinetic behaviors of canagliflozin and its metabolites. The pharmacokinetic parameters (AUC0–t, AUC0–∞, CLz/F, and Vz/F) of canagliflozin were significantly different between the CTRL and DM group rats (p < 0.05 or p < 0.01), which may subsequently cause different therapeutic effects.
Highlights
Type 2 diabetes mellitus (T2DM), a worldwide chronic disease accounting for more than 90% of all diabetic patients, is characterized by hyperglycemia due to a deficiency in insulin secretion, excessive hepatic glucose production and insulin resistance [1,2]
We developed a sensitive and effective UPLC-MS/MS quantification and semi-quantification method to simultaneously detect canagliflozin and its metabolites in rat plasma, semi-quantification method to simultaneously detect canagliflozin and its metabolites in rat plasma, respectively
We reported the pharmacokinetics of canagliflozin and transformations of its its four main metabolites in type 2 diabetic model rats, and these alternations may have an effect on four main metabolites in type 2 diabetic model rats, and these alternations may have an effect on the the application of canagliflozin in clinical therapy
Summary
Type 2 diabetes mellitus (T2DM), a worldwide chronic disease accounting for more than 90% of all diabetic patients, is characterized by hyperglycemia due to a deficiency in insulin secretion, excessive hepatic glucose production and insulin resistance [1,2]. As an active inhibitor of SGLT2, canagliflozin, a novel oral hypoglycemic agent,tubules, has been canagliflozin canasreduce the to reabsorption of filtered glucose, thereby increasing approved an adjunct diet and exercise to improve glycemic control in T2DMurinary patientsglucose in several excretion (UGE).[6,7,8]. Inducers of CYP concentration of canagliflozin in patients and healthy participants, which efficacy and UGT enzymes (e.g., rifampicin, phenytoin, barbiturates, etc)may candecrease decreasethethe plasma of canagliflozin [14].ofIncanagliflozin addition, the ofparticipants, major metabolites can clearly the concentration in pharmacokinetics patients and healthy which may decreasereflect the efficacy metabolism procession of canagliflozin in vivo [15,16] It is very important for us of canagliflozin [14].
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