Disposition of 1-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2'- (methylsulfonyl)-[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)- 1H-pyrazole-5-carboxamide (DPC 423) by Novel Metabolic Pathways. Char
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- 作者：Abdul. E. Mutlib ; John Shockcor ; Shiang-Yuan Chen ; Robert J. Espina ; Donald J. Pinto ; Michael J. Orwat ; Shimoga R. Prakash ; and Liang-Shang Gan
- 刊名：Chemical Research in Toxicology
- 出版年：2002
- 出版时间：January 2002
- 年：2002
- 卷：15
- 期：1
- 页码：48 - 62
- 全文大小：192K
- 年卷期：v.15,no.1(January 2002)
- ISSN：1520-5010
文摘
The in vitro and in vivo disposition of DPC 423 was investigated in mice, rats, dogs andhumans and the metabolites characterized by LC/MS, LC/NMR and high field-NMR. Therodents produced several metabolites that included an aldehyde (M1), a carboxylic acid (M2),a benzyl alcohol (M3), glutamate conjugates (M4 and M5), an acyl glucuronide (M6) and itsisomers; a carbamyl glucuronide (M7); a phenol (M8) and its glucuronide conjugate (M9), twoglutathione adducts (M10 and M11), a sulfamate conjugate (M12), isomers of an oximemetabolite (M13), and an amide (M14). Humans and dogs produced less complex metaboliteprofiles than rats. While unchanged DPC 423 was the major component in plasma and urinesamples, differences in the metabolic disposition of this compound among species were noted.M1 is believed to be rapidly oxidized to the carboxylic acid (M2), which forms the potentiallyreactive acyl glucuronide (M6). The formation of novel glutamate conjugates (M4 and M5)and their role in depleting endogenous glutathione have been described previously. Thecarbamyl glucuronide M7, found as the major metabolite in rats and in other species, wasconsidered nonreactive and was easily hydrolyzed to the parent compound in the presence of
-glucuronidase. The identification of GSH adducts M10 and M11 led us to postulate theexistence of at least two reactive intermediates responsible for their formation, an epoxideand possibly a nitrile oxide, respectively. Although the formation of GSH adducts such as M10from epoxides has been described before, there are no reports to date describing the existenceof a GSH adduct (M11) of an oxime. The formation of a sulfamate conjugate (M12) formed bydirect coupling of sulfate to the nitrogen of benzylamine is described. A mechanism is proposedfor the formation of the oxime (M13) that involves sequential oxidation of the benzylamine tothe corresponding hydroxylamine and nitroso intermediate. The rearrangement of the nitrosointermediate is believed to produce the oxime (M13). In vitro studies suggested that both theoxime (M13) and the aldehyde (M1) were precursors to the carboxylic acid (M2). This is thefirst demonstration of carboxylic acid formation via an oxime intermediate produced from anamine. The stability of DPC423 in plasma obtained from several species was studied. Significantspecies differences in the plasma stability of DPC 423 were observed. The formation of thealdehyde metabolite (M1) was found to be catalyzed by a semicarbazide-sensitive monoamineoxidase (SSAO) found in plasma of rabbits, dogs, and rhesus monkeys. Rat, chimpanzee, andhuman plasma did not form M1.
-glucuronidase. The identification of GSH adducts M10 and M11 led us to postulate theexistence of at least two reactive intermediates responsible for their formation, an epoxideand possibly a nitrile oxide, respectively. Although the formation of GSH adducts such as M10from epoxides has been described before, there are no reports to date describing the existenceof a GSH adduct (M11) of an oxime. The formation of a sulfamate conjugate (M12) formed bydirect coupling of sulfate to the nitrogen of benzylamine is described. A mechanism is proposedfor the formation of the oxime (M13) that involves sequential oxidation of the benzylamine tothe corresponding hydroxylamine and nitroso intermediate. The rearrangement of the nitrosointermediate is believed to produce the oxime (M13). In vitro studies suggested that both theoxime (M13) and the aldehyde (M1) were precursors to the carboxylic acid (M2). This is thefirst demonstration of carboxylic acid formation via an oxime intermediate produced from anamine. The stability of DPC423 in plasma obtained from several species was studied. Significantspecies differences in the plasma stability of DPC 423 were observed. The formation of thealdehyde metabolite (M1) was found to be catalyzed by a semicarbazide-sensitive monoamineoxidase (SSAO) found in plasma of rabbits, dogs, and rhesus monkeys. Rat, chimpanzee, andhuman plasma did not form M1.