RESUMO
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 ß-1-O-acyl glucuronide, and sipoglitazar-G2, an α-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 ß-site of sipoglitazar-G1.
Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Glucuronatos/metabolismo , Hipoglicemiantes/metabolismo , Microssomos Hepáticos/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Propionatos/metabolismo , Tiazóis/metabolismo , Alquilação , Animais , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Hidrocarboneto de Aril Hidroxilases/genética , Biocatálise/efeitos dos fármacos , Células Cultivadas , Citocromo P-450 CYP2C8 , Cães , Inibidores Enzimáticos/farmacologia , Glucuronatos/química , Glucuronídeos/química , Glucuronídeos/metabolismo , Glucuronosiltransferase/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Humanos , Hipoglicemiantes/química , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Estrutura Molecular , Oxirredução/efeitos dos fármacos , Propionatos/sangue , Propionatos/química , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Especificidade por Substrato , Tiazóis/sangue , Tiazóis/química , Uridina Difosfato Ácido Glucurônico/metabolismoRESUMO
Sipoglitazar is a novel anti-diabetic agent with triple agonistic activities on the human peroxisome proliferator-activated receptors, hPPAR-γ, -α, and -δ. The bioavailability for sipoglitazar was 95.0% and 72.6% in rats and monkeys respectively and sipoglitazar is hardly subject to first pass metabolism in either species. Following oral administration of [¹4C]sipoglitazar to rats, sipoglitazar and its metabolites were distributed to the rat tissues with relatively high concentrations in the liver and also to the target tissue, the adipose tissue. The major component was sipoglitazar in the plasma of rats and monkeys. In rats, sipoglitazar was mainly excreted into the feces via biliary excretion as sipoglitazar-G, while the major component was M-I-G in the urine and M-I in the feces of monkeys. In hepatocytes, the metabolism was not extensively advanced in rats and the main metabolites were M-I and sipoglitazar-G in humans, similar to the metabolic profile in monkeys. There was no metabolite specific for humans in vitro. In conclusion, the formation of M-I, M-I-G and sipoglitazar-G is considered to be crucial and sipoglitazar is presumed to be cleared primarily by oxidation and glucuronidation in humans, when examined in vivo and in vitro.
Assuntos
PPAR alfa/agonistas , PPAR delta/agonistas , PPAR gama/agonistas , Propionatos/administração & dosagem , Propionatos/metabolismo , Tiazóis/administração & dosagem , Tiazóis/metabolismo , Administração Oral , Animais , Humanos , Macaca fascicularis , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , PPAR alfa/metabolismo , PPAR delta/metabolismo , PPAR gama/metabolismo , Propionatos/química , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Tiazóis/química , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologiaRESUMO
Preparation and biological activity of the metabolites of the potent antihyperglycemic and antihyperlipidemic agent, (E)-4-(4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino)-4-phenylbutyric acid (TAK-559) (1), were investigated. Metabolites M-I (2), M-II (3), M-III (4) and M-IV (5) were synthesized and their biological activities were evaluated by in vitro and in vivo experiments. Compounds 2-4 activate human peroxisome proliferator-activated receptor gamma one (hPPARgamma1) and hPPARalpha, but their activities are weaker than those of TAK-559 (1). Compound 5 only activates hPPARgamma1 weakly. TAK-559 (1) showed potent in vivo plasma glucose and triglyceride lowering activities in Wistar fatty rats after intraperitoneal administration, while its metabolites (2-5) showed comparatively weak activities.