Metabolic Profile of FYX-051 (4-(5-Pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile) in the Rat, Dog, Monkey, and Human: Identification of N-Glucuronides and N-Glucosides

Abstract

ABSTRACT:FYX-051, 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile, is a novel xanthine oxidoreductase inhibitor that can be used for the treatment of gout and hyperuricemia. We examined the metabolism of FYX-051 in rats, dogs, monkeys, and human volunteers after the p.o. administration of this inhibitor. The main metabolites in urine were pyridine N-oxide in rats, triazole Nglucoside in dogs, and triazole N-glucuronide in monkeys and humans, respectively. Furthermore, N-glucuronidation and N-glucosidation were characterized by two types of conjugation: triazole N 1 -and N 2 -glucuronidation and N 1 -and N 2 -glucosidation, respectively. N 1 -and N 2 -glucuronidation was observed in each species, whereas N 1 -and N 2 -glucosidation was mainly observed in dogs. With regard to the position of conjugation, N 1 -conjugation was predominant; this resulted in a considerably higher amount of N 1 -conjugate in each species than N 2 -conjugate. The present results indicate that the conjugation reaction observed in FYX-051 metabolism is unique, i.e., N-glucuronidation and N-glucosidation occur at the same position of the triazole ring, resulting in the generation of four different conjugates in mammals. In addition, a urinary profile of FYX-051 metabolites in monkeys and humans was relatively similar; triazole N-glucuronides were mainly excreted in urine.FYX-051 (4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile) is a new xanthine oxidoreductase (XOR) inhibitor that is synthesized by Fuji Yakuhin Co., Ltd (Saitama, Japan). It is expected that this inhibitor has potential applications in the treatment of gout and hyperuricemia. This compound has more potent inhibitory effect on bovine milk XOR in vitro than allopurinol. With regard to hypouricemic effects in potassium oxonate-induced hyperuricemic rodent models, FYX-051 caused a dose-dependent reduction in serum urate concentrations. In rats, these effects of FYX-051 were approximately 30-fold more potent than those of allopurinol. In yeast RNAinduced hyperuricemic chimpanzees, FYX-051 was shown to continuously reduce the serum urate level; this implies that FYX-051 is more effective than allopurinol. Very recently, Okamoto et al. (2004) determined the X-ray crystal structure of the XOR-FYX-051 complex. They showed that FYX-051 binds to the active-site molybdenum by a covalent linkage, similar to allopurinol. In contrast to the purine ring structure of allopurinol, FYX-051 has a unique pyridine-triazolecyanopyridine structure that excludes an oxygen atom.Preliminary in vitro metabolic studies on FYX-051 were carried out using animal and human liver microsomes. In these studies, the oxidative metabolites and conjugates of FYX-051 were observed; however, their structures remained to be elucidated. Therefore, we attempted to identify these metabolites. Authentic samples were synthesized for determining the oxidative metabolites, and conjugates were purified from the urine of mammals after dosing of FYX-051.In the present study, we characterized ...

Excretion, Metabolism, and Pharmacokinetics of CP-945,598, a Selective Cannabinoid Receptor Antagonist, in Rats, Mice, and Dogs

“…NGlucosylation of xenobiotics in mammals has been observed for a limited number of drugs such as phenobarbital (Soine et al, 1994;Paibir et al, 2004), 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile (FYX-051) (Nakazawa et al, 2006) and 5-aminosalicylic acid (Tjornelund et al, 1991), but to our knowledge, Nribosylation has not been reported previously. These ribose conjugates were detected only in feces and not observed in bile; therefore, it is likely the formation of these metabolites was due to gut microbial metabolism.…”

Biosynthesis and Identification of an N-Oxide/N-Glucuronide Metabolite and First Synthesis of an N-O-Glucuronide Metabolite of Lu AA21004

“…Chemical shifts and coupling constants of tertiary N-glucuronides and ␤-anomers are found at 5.33 to 6.31 ppm and 8.3 to 9.5 Hz, respectively (Andersen et al, 1989;Keating et al, 2006;Nakazawa et al, 2006;Yan et al, 2006), which are at lower field (higher parts per million) than the anomeric proton of N-O-glucuronides (range of chemical shift 4.54 -4.84 ppm and coupling constants of 8.4 -9 Hz) (Straub et al, 1988;Delbressine et al, 1992;Turgeon et al, 1992;Schaber et al, 2001;and Miller et al, 2004). The N-Oglucuronide 3 fits the published range.…”

Characterization ofN-Glucuronidation of 4-(5-Pyridin-4-yl-1H-[1,2,4]triazol-3-yl) pyridine-2-carbonitrile (FYX-051): A New Xanthine Oxidoreductase Inhibitor

“…The FYX-051 glucuronides were quantified by LC-MS/MS, according to a previously described method (Nakazawa et al, 2006) with a slight modification. A 5-l aliquot of the supernatant was injected into a LC-MS/MS unit consisting of a 1100 series high-performance liquid chromatography system (Agilent Technologies, Palo Alto, CA) and API 3000 (Applied Biosystems/MDS Sciex, Foster City, CA).…”

“…The metabolism of FYX-051 has been evaluated in rats, dogs, monkeys, and humans; its major metabolites in humans were identified as triazole N 1 -and N 2 -glucuronides, and they were excreted into urine at 43.3 and 16.1% of the dose, respectively, after the oral administration of FYX-051 (Nakazawa et al, 2006).…”

“…1) was synthesized by Fuji Yakuhin Co., Ltd. (Saitama, Japan). Two FYX-051 N-glucuronides (triazole N 1 -and N 2 -glucuronide) were purified from human urine by Fuji Yakuhin Co., Ltd., as described previously (Nakazawa et al, 2006) (Fig. 1).…”