title: Metabolic fate of sipoglitazar, a novel oral PPAR agonist with activities for PPAR-γ, -α and -δ, in rats and monkeys and comparison with humans in vitro.
abstract: 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.
authors: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa. Nishihara_Mitsuhiro@takeda.co.jp
authors: Mitsuhiro
authors: M
authors: Nishihara
authors: Miyako
authors: M
authors: Sudo
authors: Hidenori
authors: H
authors: Kamiguchi
authors: Naohiro
authors: N
authors: Kawaguchi
authors: Yoshihiro
authors: Y
authors: Maeshiba
authors: Yutaka
authors: Y
authors: Kiyota
authors: Junzo
authors: J
authors: Takahashi
authors: Yoshihiko
authors: Y
authors: Tagawa
authors: Takahiro
authors: T
authors: Kondo
authors: Satoru
authors: S
authors: Asahi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011422:Propionates / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013844:Thiazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; D011422:Propionates; D013844:Thiazoles; C572168:sipoglitazar