An unusual metabolic pathway of sipoglitazar, a novel antidiabetic agent: cytochrome P450-catalyzed oxidation of sipoglitazar acyl glucuronide.
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 β-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 β-site of sipoglitazar-G1.
Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. nishihara_mitsuhiro@takeda.co.jp
Mitsuhiro
M
Nishihara
Miyako
M
Sudo
Naohiro
N
Kawaguchi
Junzo
J
Takahashi
Yutaka
Y
Kiyota
Takahiro
T
Kondo
Satoru
S
Asahi
D000478:Alkylation; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055162:Biocatalysis / Q000187:drug effects; D002478:Cells, Cultured; D065727:Cytochrome P-450 CYP2C8; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005965:Glucuronates / Q000737:chemistry / Q000378:metabolism*; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D015394:Molecular Structure; D010084:Oxidation-Reduction / Q000187:drug effects; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D011422:Propionates / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013379:Substrate Specificity; D013844:Thiazoles / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism
D004791:Enzyme Inhibitors; D005965:Glucuronates; D020719:Glucuronides; D007004:Hypoglycemic Agents; D047492:Peroxisome Proliferator-Activated Receptors; D011422:Propionates; D011994:Recombinant Proteins; D013844:Thiazoles; D014535:Uridine Diphosphate Glucuronic Acid; C572168:sipoglitazar; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D014453:Glucuronosyltransferase