Kinetics of the Absorption, Distribution, Metabolism and Excretion of Lobeglitazone, a Novel Activator of Peroxisome Proliferator-activated Receptor Gamma in Rats

Abstract

This primary goal of this study was to determine the biopharmaceutical properties of lobeglitazone (LB) in rats. LB is a novel thiazolidinedione (TZD)-based activator of the peroxisome proliferator-activated receptor gamma (PPAR-γ) that interacted multidrug resistance protein (MDR1) and organic anion transporting polypeptide (OATP1B1) transporters in a parallel artificial membrane permeability assay (PAMPA) and Madin-Darby canine kidney (MDCK) cells permeability assays. The present findings demonstrate that LB had an IC50 value of approximately 12.5 ± 3.61 µM in MDR1-expressing MDCK cells, adequate stability in rat liver microsomes (56% remaining at 30 min), and appeared to be metabolized by cytochrome P450 (CYP). A CYP inhibitory potency experiment indicated that LB was primarily interacted with CYP1A2, CYP2C9 and CYP2C19. In addition, LB had an absolute bioavailability of approximately 95% after oral administration, which indicates that it was readily absorbed, and exhibited linear pharmacokinetics following the intravenous (IV) administration of 0.5-2 mg/kg. Rat plasma samples were processed using a fast flow protein precipitation (FF-PPT) method and then introduced onto an LC-MS/MS system for quantification using the validated assay. The primary distribution site for LB was the liver, but it was also distributed to the heart, lungs, and fat tissue. The excretion values of LB to the urine, bile, feces, and intestine were relatively insignificant (< 10% of the dose). The present findings suggest that, although LB interacts with several drug transporters and metabolizing enzymes, its pharmacokinetics were linear with a high oral bioavailability. The formation of the metabolites of LB by demethylation and hydroxylation after incubation of LB within rat liver microsomes was elucidated. The plasma concentrations of LB after oral administration of 0.1-10 mg/kg were markedly higher (3.5-4.5 fold) in female rats. An in vitro metabolic stability study found that the CLint value for females was approximately 29% of the value for males. Similarly, the apparent oral clearance for females was approximately 20% of that for males. These observations suggested that there are clear gender differences in the pharmacokinetics and hepatic metabolism for LB in rats. These kinetics of the absorption, distribution, metabolism and excretion of LB demonstrated the characterization of LB to develop as an oral diabetes agent.