Metabolism and disposition of 14C-labeled peliglitazar in humans.
The metabolism and disposition of dual (14)C-labeled peliglitazar, a dual α/γ peroxisome proliferator-activated receptor activator, was investigated in 10 healthy male subjects with and without bile collection (groups 1 and 2) after a single 10-mg oral dose. Serial blood samples, urine, and feces (0-240 h) as well as bile samples (3-8 h after dosing from group 2 subjects) were collected. The maximum plasma concentration (C(max)) of drug was reached at approximately 1 h and the elimination half-life (t(1/2)) was approximately 3.5 h. The exposure to drug metabolites (C(max) and area under the plasma concentration versus time curve) was not significantly different between the two groups. The parent compound and its 1-O-β-acyl-glucuronide conjugate were the major components in plasma; other circulating metabolites, including several other glucuronide conjugates, were minor components at all time points. The major portion of the radioactive dose was recovered in feces (94% for group 1 and 32% for group 2). Approximately 24% of the radioactive dose was recovered in the bile from group 2 subjects, nearly all of which was assigned as glucuronides of peliglitazar and its oxidative metabolites (M14, M14a, M14b, M15, M15a, M15b, and M17). In contrast, fecal samples contained peliglitazar and its oxidative metabolites resulting from aliphatic/aryl hydroxylation, and O-demethylation. These results suggested that the major clearance pathway of peliglitazar was through biliary elimination of glucuronide conjugates, which were hydrolyzed to peliglitazar and its oxidative metabolites in the intestines before excretion.
Pharmaceutical Candidate Optimization, Discovery and Development, Bristol-Myers Squibb, Princeton, NJ 08543-4000, USA. lifei.wang@bms.com
Lifei
L
Wang
Carey
C
Munsick
Sean
S
Chen
Samuel
S
Bonacorsi
Peter T
PT
Cheng
W Griffith
WG
Humphreys
Donglu
D
Zhang
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D001711:Biotransformation; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D005998:Glycine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D015394:Molecular Structure; D010080:Oxazoles / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D014018:Tissue Distribution; D055815:Young Adult
D002250:Carbon Radioisotopes; D010080:Oxazoles; D047492:Peroxisome Proliferator-Activated Receptors; C557782:peliglitazar; D005998:Glycine