An Unusual Metabolic Pathway of Sipoglitazar, a Novel Antidiabetic Agent: Cytochrome P450-Catalyzed Oxidation of Sipoglitazar Acyl Glucuronide

Abstract

ABSTRACT:Animal pharmacokinetic studies of sipoglitazar, a novel antidiabetic agent, showed that the deethylated metabolite (M-I) and the glucuronide conjugate of sipoglitazar (sipoglitazar-G) appeared to be the key metabolites in the elimination process. M-I was also measured as the main metabolite in the plasma of humans administered sipoglitazar. In vitro metabolic studies were performed to investigate the metabolic pathways from sipoglitazar to M-I in humans. The metabolic profile with human hepatocytes and hepatic microsomes indicated that M-I was not formed directly from sipoglitazar and that sipoglitazar-G was involved in the metabolism from sipoglitazar to M-I. Further studies of the metabolism of sipoglitazar-G revealed that the properties of the glucuronide conjugate and its metabolism are as follows: high-performance liquid chromatography, liquid chromatography-tandem mass spectrometry, and NMR analyses showed that sipoglitazar-G was composed of two glucuronides, sipoglitazar-G1, a ␤-1-O-acyl glucuronide, and sipoglitazar-G2, an ␣-2-O-acyl glucuronide. The stability study of these glucuronides suggested that sipoglitazar-G1 could be converted to sipoglitazar-G2 and sipoglitazar, but sipoglitazar-G2 could not be converted to sipoglitazar-G1. The oxidative metabolic study of sipoglitazar-G1 and -G2 with human hepatic microsomes and cytochrome P450-expressing microsomes revealed that M-I was formed only from sipoglitazar-G1, not from sipoglitazar-G2, and that CYP2C8 was mainly involved in this process. From these results, it is shown that the metabolic pathway from sipoglitazar to M-I is an unusual one, in which sipoglitazar is initially metabolized to sipoglitazar-G1 by UDP-glucuronosyltransferase and then sipoglitazar-G1 is metabolized to M-I by O-dealkylation by CYP2C8 and deconjugation. Sipoglitazar-G2 is sequentially formed by the migration of the ␤-site of sipoglitazar-G1.

A model-based approach to analyze the influence of UGT2B15 polymorphism driven pharmacokinetic differences on the pharmacodynamic response of the PPAR agonist sipoglitazar

“…Sipoglitazar, a novel orally available peroxisome proliferator activated receptor (PPAR) agonist with activities for PPAR α, δ, and γ, was targeted for Type 2 Diabetes Mellitus (T2DM) as a next generation insulin sensitizer. The compound undergoes Phase II biotransformation by conjugation through UDP‐glucuronosyltransferase (UGT) . Following a population pharmacokinetic analysis, UGT2B15 genotype was found to be a covariate for the clearance (CL) of sipoglitazar both in healthy subjects and T2DM patients .…”

“…The compound undergoes Phase II biotransformation by conjugation through UDP-glucuronosyltransferase (UGT). 1 Following a population pharmacokinetic analysis, UGT2B15 genotype was found to be a covariate for the clearance (CL) of sipoglitazar both in healthy subjects and T2DM patients. 2 Higher plasma exposure of sipoglitazar was observed in the UGT2B15 Ã 2/ Ã 2 genotype than subjects homozygous for the wild-type allele UGT2B15 Ã 1/ Ã 1 (3.3-fold higher) or heterozygous allele UGT2B15 Ã 1/ Ã 2 (2.2-fold higher).…”

Glucuronides as Potential Anionic Substrates of Human Cytochrome P450 2C8 (CYP2C8)

“… Deethylated sipoglitazar (M1) is detected as the major circulating metabolite following oral administration of sipoglitazar to human subjects. Although M1 appears to be a typical CYP-catalyzed product, investigation into its formation using HLM and human hepatocytes suggests that glucuronidation of sipoglitazar is a prerequisite for the dealkylation step . Phenotyping studies have revealed that sipoglitazar is converted to sipoglitazar-β-1- O -acyl glucuronide (SG1) by UGT2B15 and the formation of deethylated SG1 is exclusively catalyzed by CYP2C8.…”

“…Interestingly, sipoglitazar-α-2- O -acyl glucuronide (SG2), which is the acyl migration product of SG1 detected in the bile of rats, is not prone to CYP2C8-catalyzed oxidation. These findings led the authors to speculate that formation of M1 involves the dealkylation of the glucuronide SG1 to deethylated SG1, followed by hydrolysis of the glucuronide intermediate …”

Evaluation of the Impact of UGT Polymorphism on the Pharmacokinetics and Pharmacodynamics of the Novel PPAR Agonist Sipoglitazar

“…Sipoglitazar, a novel orally available, peroxisome proliferator–activated receptor (PPAR) agonist with activities for PPAR α, δ, and γ, was targeted for type 2 diabetes mellitus (T2DM). The compound undergoes phase II biotransformation by conjugation catalyzed by UGT . During phase I clinical trials, a bimodal or multimodal distribution of exposure/clearance appeared to be more likely than a normal distribution; this was later evaluated using in vitro data and found to be related to a polymorphism of the UGT2B15 enzyme.…”