Identification of glutathione-derived metabolites from an IP receptor antagonist.
The metabolic fate of three aromatic carboxylic acid analogs under evaluation as prostaglandin I2-preferring receptor antagonists was studied. The initial analog with unsubstituted phenyl groups was subject to a complex set of aromatic oxidative biotransformations. By introduction of one or two fluorines, these pathways were inhibited. All three analogs were metabolized to a wide variety of carboxylic acid conjugates. Among these were several conjugates formed via secondary metabolism and oxidation of acyl glutathione intermediates. Two of the structure classes, represented by the S-methyl-N-cysteinylglycine conjugate and the N-cysteinylglycine disulfide conjugates, have been described only rarely in the literature. The related S-oxide of the S-methyl-N-cysteinylglycine conjugate and the N,S-bis-acyl derivative of cysteinylglycine are here described for the first time as conjugate metabolites of carboxylic drugs.
Fitch
William L
WL
DMPK Department, Roche Palo Alto, LLC, 3431 Hillview Ave., Palo Alto, CA 94304, USA. Bill.fitch@roche.com
Berry
Pamela W
PW
Tu
Yaping
Y
Tabatabaei
Ali
A
Lowrie
Lee
L
Lopez-Tapia
Francisco
F
Liu
Yanzhou
Y
Nitzan
Dov
D
Masjedizadeh
Mohammad R
MR
Varadarajan
Aravamuthan
A
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D011464:Epoprostenol / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D000882:Haplorhini; D022781:Hepatocytes / Q000378:metabolism; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007553:Isotope Labeling; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008970:Molecular Weight; D010084:Oxidation-Reduction; D010477:Perfusion; D051381:Rats; D044006:Receptors, Epoprostenol / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet
D007202:Indicators and Reagents; D044006:Receptors, Epoprostenol; D011464:Epoprostenol; D005978:Glutathione