Biotransformation of carbon-14-labeled muraglitazar in male mice: interspecies difference in metabolic pathways leading to unique metabolites.
Muraglitazar (Pargluva; Bristol-Myers Squibb), a dual alpha/gamma peroxisome proliferator-activated receptor activator, is under development for treatment of type 2 diabetes. This study describes the biotransformation profile of carbon-14-labeled muraglitazar in plasma, urine, feces, and bile samples from male CD-1 mice [intact and bile duct cannulation (BDC)] after single oral doses of 1 and 40 mg/kg. The major drug-related component circulating in mouse plasma was the parent compound for up to 4 h postdose. Similar to excretion profiles of muraglitazar in humans, monkeys, and rats, urinary excretion was the minor and fecal excretion via the biliary route was the major elimination pathway for muraglitazar in mice. The parent compound was a minor component in urine, bile, and feces, indicating that muraglitazar was extensively metabolized in mice. Major biotransformation pathways of muraglitazar in mice included taurine conjugate formation, acyl glucuronidation, hydroxylation, and O-dealkylation. In addition to those metabolites previously identified in humans, monkeys, and rats (M1-M21), several unique metabolites identified in mice included taurine conjugates (M24, M25, M26a,b,c, and M31), oxazole-ring-opened metabolites (M27 and M28), glutathione conjugates (M29a,b and M30), a dihydroxylated metabolite (M32), hydroxylated metabolites (M33 and M35), and a dehydrogenated metabolite (M34). The taurine conjugate of muraglitazar, M24, was a major metabolite in mice, accounting for 12 to 15% of the total dose in BDC mice or 7 to 12% of the total dose in intact mice. None of these taurine and glutathione conjugates were found in the bile samples of humans, monkeys, or rats.
Li
Wenying
W
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Co., Princeton, NJ 08543, USA.
Zhang
Donglu
D
Wang
Lifei
L
Zhang
Hao
H
Cheng
Peter T
PT
Zhang
Duxi
D
Everett
Donald W
DW
Humphreys
W Griffith
WG
D000818:Animals; D001646:Bile / Q000378:metabolism; D001652:Bile Ducts / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D005978:Glutathione / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000882:Haplorhini; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D010080:Oxazoles / Q000493:pharmacokinetics*; D051381:Rats; D013045:Species Specificity; D013056:Spectrophotometry, Ultraviolet; D013654:Taurine / Q000378:metabolism
D007004:Hypoglycemic Agents; D010080:Oxazoles; D013654:Taurine; D005978:Glutathione; D005998:Glycine; C500085:muraglitazar