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

The identification of lobeglitazone metabolites in rat liver microsomes and the kinetics of the in vivo formation of the major metabolite M1 in rats

“…Furthermore, we found that the hepatic 9 metabolism of LB was gender-specific in rats [7]; Considering the fact that the metabolism of LB 10 metabolism is a major determinant of its pharmacokinetics, the gender specific metabolism may lead 11 to differences in the therapeutic effect of LB, depending on the gender of the subject. Interestingly, we 12 found that the metabolism of LB, other than the CYP-mediated biotransformation (e.g., the 13 conjugation of LB with glucuronides) was apparently absent [1], suggesting that LB is largely 14 metabolized via CYP isozymes and that this route is the major determinant in the elimination and the 15 pharmacokinetics. Despite the kinetic importance of LB metabolism, however, the metabolic pathway 16 for this TZD PPAR is not known with certainty.…”

“…Compared 3 with other PPAR-γ activators, the affinity of LB towards PPAR-γ [2-6] was found to be higher, 4 suggesting that a lower dose could be used and, accordingly, adverse cardiovascular reactions, a 5 common form of toxicity for thiazolidinediones (TZDs) PPARs, may be reduced for LB. 6 We recently reported that the combined extent of the excretion of LB to the bile, urine and 7 intestine was remarkably low (i.e., less than 10% of the dose was excreted), suggesting that the major 8 route of elimination for the drug involves its metabolism [1]. Furthermore, we found that the hepatic 9 metabolism of LB was gender-specific in rats [7]; Considering the fact that the metabolism of LB 10 metabolism is a major determinant of its pharmacokinetics, the gender specific metabolism may lead 11 to differences in the therapeutic effect of LB, depending on the gender of the subject.…”

“…1 Lobeglitazone (LB), an activator for peroxisome proliferator-activated receptors (PPARs), is a 2 drug that has recently been developed in Korea for use in the treatment of diabetes [1]. Compared 3 with other PPAR-γ activators, the affinity of LB towards PPAR-γ [2-6] was found to be higher, 4 suggesting that a lower dose could be used and, accordingly, adverse cardiovascular reactions, a 5 common form of toxicity for thiazolidinediones (TZDs) PPARs, may be reduced for LB.…”

“…For the case of the calibration curves for LB in RLM, the detector response was also linear over the concentration range of 0.1-50 µM with a correlation coefficient in excess of 0.999 for three 1 batches of calibration curves. In these samples, the LOQs for LB were 0.1 µM (i.e., in 480.2 ng/mL).…”

“…Information-dependent acquisition (IDA) criteria 26 were employed to automatically trigger the acquisition of the EPI scan to acquire full-scan MS/MS spectra of the predicted metabolite ions. Target screening was accomplished using a MRM scan to 1 identify the analytes. The MRM transition of LB was used to configure 47 MRM ion pairs covering 2 the most common phase I and II metabolic reactions with a dwelling time of 40 ms each using an 3 Analyst script.…”