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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

Research Laboratories 2, Fuji Yakuhin Co., Ltd., Saitama, Japan

(Received June 28, 2006; accepted August 14, 2006)

	Abstract

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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 N-glucoside 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 N₁- and N₂-glucuronidation and N₁- and N₂-glucosidation, respectively. N₁- and N₂-glucuronidation was observed in each species, whereas N₁- and N₂-glucosidation was mainly observed in dogs. With regard to the position of conjugation, N₁-conjugation was predominant; this resulted in a considerably higher amount of N₁-conjugate in each species than N₂-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.

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 the structure of FYX-051 metabolites and determined the urinary profile of FYX-051 metabolites among rats, dogs, monkeys, and humans in vivo.

	Materials and Methods

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Chemicals. ¹⁴C-FYX-051 (Fig. 1) was synthesized by Daiichi Pure Chemicals Co., Ltd. (Ibaraki, Japan). In brief, 4-[¹⁴C-cyano]pyridine was prepared by reaction of sodium pyridine-4-sulfonate with ¹⁴C-KCN, and ¹⁴C-FYX-051 was finally prepared by condensation reaction of 4-[¹⁴C-cyano]pyridine and 2-cyanoisonicotinic acid hydrazide in the presence of sodium methoxide. Its specific radioactivity and radiochemical purity were 8.70 MBq/mg and 98.7% or more, respectively. FYX-051, pyridine N-oxide, and pyridine hydroxide forms of FYX-051 (N-oxide and hydroxide) were synthesized by Fuji Yakuhin Co., Ltd (Fig. 1). In brief, N-oxide was synthesized from 4-cyanopyridine-N-oxide and 2-cyanoisonicotinic acid hydrazide in the same way as ¹⁴C-FYX-051 synthesis. Hydroxide was prepared by acylation of N-oxide followed by hydrolysis. All the other reagents were of the highest or analytical grade commercially available and purchased from Kishida Chemical Co (Osaka, Japan).

View larger version (17K): [in this window] [in a new window]   FIG. 1. Chemical structure of FYX-051 and its metabolites of N-oxide and hydroxide. *, 14C-labeled position

View larger version (22K): [in this window] [in a new window]   FIG. 2. MS spectra of the FYX-051 glucuronides and glucosides analyzed in the negative ion mode for glucuronides and in the positive ion mode for glucoside.

Purification of Glucuronides and Glucosides. The urine samples obtained from human volunteers and dogs were individually lyophilized for the isolation of glucuronides and glucosides, respectively. To remove insoluble materials, methanol was added to the residue and extracted. The collected methanol fraction was evaporated and dissolved in a methanol/chloroform mixture (1:1, v/v). After the insoluble materials were removed, the sample was separated using a silica gel chromatographic open column (50 mm i.d. x 400 mm, silica gel 60; Merck, Darmstadt, Germany). The elution was carried out using a methanol/chloroform mixture (1:1, v/v), and the glucuronide or glucoside fraction was collected. After each conjugate fraction (glucuronides and glucosides) was evaporated, methanol was added to the residue. Preparative high-performance liquid chromatography (HPLC) using a 2690 separation module (Waters Co., Milford, MA) was performed on an Inertsil ODS-3 column (10 mm i.d. x 250 mm, 5 µm; GL Sciences Inc., Tokyo, Japan) with a mobile phase containing a mixture of 0.5% acetic acid and acetonitrile (90:10 or 85:15, v/v). The four collected fractions were repeatedly purified by preparative HPLC, and approximately 10 mg of each conjugate (glucuronides A and B and glucosides A and B) was obtained. Finally, about 5 mg of each purified conjugate was used for the NMR analysis.

Structure Characterization of Glucuronides and Glucosides. Liquid chromatography/mass spectrometry. The purified conjugates were subjected to liquid chromatography/mass spectrometry (LC/MS) analysis using the 1100 HPLC system (Agilent Technologies, Palo Alto, CA) and API150EX (Applied Biosystems/MDS Sciex, Foster City, CA). HPLC was carried out in the same manner as described under Measurement of FYX-051 Metabolites in Urine. Ionization was conducted using a turbo ion spray and negative ion mode at 300°C for glucuronides A and B, and positive ion mode at 300°C for glucosides A and B. Nitrogen was used as a nebulizing and heating gas, and a full-scan analysis at m/z 200 to 500 was conducted.

NMR. ¹H NMR and ¹³C NMR spectra of glucuronides and glucosides were obtained on the UNITY INOVA 600 spectrometer (Varian, Palo Alto, CA) and probes (proton: PFG triple resonance ¹H, carbon: 15N-31P broadband, 5-mm sample tube) at 25°C, with dimethyl sulfoxide-d₆ as the solvent. Residual solvent signals were used as internal chemical shift references for proton (_{trimethyl silane} = 0.00 ppm) and carbon (_{trimethyl silane} = 0.00 ppm for glucuronides and _{dimethyl sulfoxide} = 39.5 ppm for glucosides) spectra. J values are represented in Hz. The signals were assigned using two-dimensional proton-proton [correlation spectroscopy (COSY) and nuclear Overhauser effect spectroscopy (NOESY)] and proton-carbon [heteronuclear single quantum coherence (HSQC) and heteronuclear multiple bond coherence (HMBC)] spectra. The combination position was considered as the triazole ring or the pyridine ring and analyzed from the assignment data of FYX-051.

Measurement of FYX-051 Metabolites in Urine. Rats and dogs. For the measurement of radioactive metabolites in the rats and dogs, methanol was added to the urine sample and subsequently removed by precipitation. The resultant supernatant was evaporated to dryness and subjected to radio-HPLC analysis. The residue was dissolved in methanol and chromatographed using a 2690 separation module (Waters Co.) and a Mightysil RP-18 column (4.6 mm i.d. x 250 mm, 5 µm; Kanto Chemical Co., Inc., Tokyo, Japan) and gradient flow. The initial mobile phase was 90% 20 mM potassium dihydrogen phosphate (pH 4.0) and 10% acetonitrile for 10 min, and the flow rate was 1.0 ml/min. The percentage of acetonitrile was increased in a linear manner up to 13% at 10 to 13 min, up to 25% at 25 to 35 min, and up to 60% at 40 to 60 min. The column temperature was maintained at 40°C, and radiodetection was carried out using FLO-ONE/525TR (Packard Co., Meriden, CT). Scintillator (Flo-Scint II; Packard Co.) was delivered to the HPLC eluate at a 3-fold flow rate of the mobile phase. As for the radioactive recovery from the urine sample, the radioactivity in each supernatant and precipitation was measured using a 2500TR liquid scintillation counter (Packard Co.), and the recovery was calculated using the following equation: recovery (%) = supernatant (dpm)/[supernatant (dpm) + precipitation (dpm)] x 100. The recovery of radioactivity from the urine was 99% or more.

Monkeys and human volunteers. For the measurement of FYX-051, N-oxide, and hydroxide, the urine samples were extracted with ethyl acetate. The collected organic fraction was evaporated and dissolved in 50% methanol. For estimating glucuronides and glucosides, methanol was added to the urine samples and subsequently removed by precipitation. These prepared samples were analyzed by LC/tandem mass spectrometry (MS/MS) for FYX-051, glucuronides, and glucosides and by LC/MS for N-oxide and hydroxide (1100 HPLC system, Agilent Technologies; API3000 or API150EX, Applied Biosystems/MDS Sciex). HPLC separations were carried out using a Mightysil RP-18 GP column (2.0 mm i.d. x 150 mm, 5 µm) and eluted at a flow rate of 0.2 ml/min. The elution was carried out using a 10 mM ammonium acetate/methanol mixture (45:55, v/v) for FYX-051, 0.5% acetic acid/acetonitrile mixture (81:19, v/v) for N-oxide and hydroxide, and 0.5% acetic acid/acetonitrile mixture (83:17, v/v) for glucuronides and glucosides. The column temperature was maintained at 35°C. Using nitrogen as a nebulizing and heating gas, ionization was conducted with a turbo ion spray and negative ion mode at 550°C for FYX-051, at 400°C for N-oxide and hydroxide, at 450°C for glucuronides, and a positive ion mode at 450°C for glucosides. FYX-051 and its metabolites were analyzed in the selected reaction monitoring mode (FYX-051: m/z 247 219; N-oxide and hydroxide: m/z 263; glucuronides: m/z 423 247; glucosides: m/z 411 249). All the LC/MS/MS and LC/MS data were integrated via Analyst 1.3.1 software (Applied Biosystems/MDS Sciex).

View larger version (17K): [in this window] [in a new window]   FIG. 3. Proton NMR spectra of the FYX-051 glucuronides and glucosides. The protons were assigned using two-dimensional COSY and NOESY analysis.

	Results

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Identification of Glucuronides and Glucosides. Purified glucuronides and glucosides were analyzed by LC/MS. The negative ion electrospray MS spectra of glucuronides A and B indicated the presence of parent ions at m/z 423.3 and 423.1 ([M – H]^–), respectively, and of fragment ions at m/z 247.0 and 247.4 ([M – H – 176]^–) (Fig. 2). The positive ion electrospray spectra of glucosides A and B indicated the presence of parent ions at m/z 411.2 and 411.4 ([M + H]⁺), respectively, and of fragment ions at m/z 249.3 and 249.1 ([M + H – 162]⁺) (Fig. 2). These data suggest that a glucuronic acid or glucose molecule was directly bound to the pyridine or triazole ring of FYX-051.

The structure of two types of glucuronides and glucosides was determined by ¹H NMR and ¹³C NMR analysis. The assignments of proton and carbon chemical shift regarding FYX-051 and its conjugates are summarized in Table 1, and the proton NMR spectra of each conjugate are shown in Fig. 3. These data suggest that glucuronide A and glucuronide B signals in the downfield region of the spectra originated from FYX-051 showed similar chemical shifts as those of glucoside A and glucoside B, respectively. These conjugates were classified into two modalities; one group was glucuronide A and glucoside A, and the other group was glucuronide B and glucoside B. These data indicate that glucuronide A and glucoside A bound to FYX-051 at the same position, whereas glucuronide B and glucoside B also had the same binding position. With regard to the binding position of sugars, glucuronic acid and glucose bound to FYX-051 at position 1' with the ß type because the coupling constant J from ¹H NMR analysis was 8.3 Hz for glucuronides A and B and 8.9 Hz for glucosides A and B.

View larger version (27K): [in this window] [in a new window]   FIG. 4. Chemical structure of the FYX-051 glucuronides and glucosides, including the numbering of carbon atoms, characteristic long-range couplings from H1' observed in the HMBC spectrum (solid arrow), and NOE at the adjacent H1' observed in the NOESY spectrum (dotted arrow).

Urinary Profile of FYX-051 Metabolites. After the p.o. administration of ¹⁴C-FYX-051 at a dose of 1 mg/kg to rats, the radioactivity in urine and feces was 30.4 and 40.9% of the dose, respectively, within 24 h (unpublished data). Up to 24 h after administration, the composition of FYX-051, N-oxide, and hydroxide in urine was 0.8, 46.5, and 11.3%, respectively (Fig. 5). N₁- and N₂-glucuronide and N₁-glucoside were less than 3%, and other minor metabolites were also detected. In dogs, the radioactivity in urine and feces was 18.8 and 67.0%, respectively, within 24 h after the p.o. administration of ¹⁴C-FYX-051 at a dose of 1 mg/kg (unpublished data). The composition of FYX-051 and N-oxide in urine collected up to 24 h postdosing was 0.6 and 12.0%, respectively (Fig. 5). Two glucosides were detected, and the composition of N₁- and N₂-glucoside was 37.4 and 16.3%, respectively. Furthermore, the composition of N₁- and N₂-glucuronide and hydroxide was 5.7, 1.8, and 1.1%, respectively. After the p.o. administration of FYX-051 at a dose of 1 mg/kg to monkeys, the excretion of N₁- and N₂-glucuronide in urine was 39.7 and 8.2% of the dose, respectively, within 24 h (Table 2). The excretion of FYX-051 and N-oxide was 0.4 and 0.1%, respectively. In the human volunteers, the excretion of N₁- and N₂-glucuronide in urine was 43.3 and 16.1% of the dose within 24 h after the p.o. administration of FYX-051 at a dose of 120 mg (Table 2). FYX-051 and hydroxide was 0.1% or less in urine collected up to 24 h postdosing. No glucosides could be detected in monkeys and humans.

View larger version (21K): [in this window] [in a new window]   FIG. 5. Radio-HPLC chromatograms of FYX-051 and its metabolites in urine (0–24 h) after the p.o. administration of 14C-FYX-051 at a dose of 1 mg/kg to male rats or dogs. A, reference sample (UV detection at 276 nm); B, rat urine; C, dog urine.

	Discussion

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The N-glucuronidation metabolism of xenobiotics has been reviewed in Drug Metabolism and Disposition (Chiu and Huskey, 1998; Franklin, 1998; Green and Tephly, 1998; Hawes, 1998; Kassahun et al., 1998; Zenser et al., 1998). Furthermore, Radominska-Pandya et al. (1999) summarized the glucuronidation of endogenous and xenobiotic substrates. N-glucuronidation of xenobiotics was classified into aliphatic and aromatic conjugations, and the latter consisted of conjugates such as pyridine, pyridazine, pyrimidine, imidazole, triazole, and tetrazole N-glucuronidation. Indeed, few cases of triazole N-glucuronidation, such as posaconazole and a model compound of methyl biphenyl triazole, were reported (Chiu and Huskey, 1998; Krieter et al., 2004). N-Glucuronidation that occurs individually at two sites of one aromatic ring was shown by Chiu and Huskey (1998) using a model compound of methyl biphenyl 1,2,3-triazole, and by Yan et al. (2006) in an in vitro study of tyrosine kinase inhibitor (JNJ-10198409).

On the other hand, in mammals, drug metabolism via glucosidation generally occurs less than glucuronidation, and the occurrence of N-glucosidation reaction is less than that of O-glucosidation. Furthermore, N-glucosidation of xenobiotics could also be classified into aliphatic and aromatic conjugations. Aliphatic N-glucosidation in mammals has been documented for a limited number of drugs such as phenobarbital, amobarbital, pentobarbital, bromfenac, and sulfonamides (Paulson et al., 1981; Carro-Ciampi et al., 1985; Ahmad and Powell, 1988; Soine et al., 1990, 1994; Kirkman et al., 1998; Paibir et al., 2004). However, aromatic N-glucosidation is not common. The only triazole N-glucoside that was generated at one position of the triazole ring (N₁-glucosidation) was reported by Duggan et al. (1974).

With regard to the conjugation position of glucuronidation and glucosidation, Neighbors and Soine (1995) showed that these conjugations occurred at the same position of the pyrimidinetrione ring of phenobarbital after p.o. administration in mice. In addition, O-glucuronide and O-glucoside were generated at the same position of pranoprofen in mice (Arima and Kato, 1990), although this is the case of an acyl conjugate. These observations strongly suggest that glucuronidation and glucosidation may occur at the same position of a chemical structure in mammals. To the best of our knowledge, the generation of aromatic N-glucuronide and N-glucoside at the same position of the aromatic ring has not been reported. The conjugation reaction observed in the metabolism of FYX-051 appears to be unique.

With respect to the enzymatic hydrolysis of FYX-051 N-glucuronides, N₁- and N₂-glucuronide was hydrolyzed completely by Escherichia coli ß-glucuronidase but not by Helix pomatia ß-glucuronidase. Huskey et al. (1994) reported a similar phenomenon of methyl biphenyl 1,2,3-triazole-N₁-glucuronide. By using three types of ß-glucuronidases derived from bovine liver, H. pomatia, and E. coli, Kowalczyk et al. (2000) showed that aliphatic quaternary ammonium-linked glucuronides were hydrolyzed only by E. coli ß-glucuronidase. These results suggest that the both aliphatic N-glucuronide and aromatic N-glucuronide were resistant to enzymatic degradation by some types of ß-glucuronidases.

In urinary profile of FYX-051 metabolites in rats, N-oxide was mainly observed, and hydroxide, N₁- and N₂-glucuronide, and N₁-glucoside were also detected. In dogs, the main metabolite in urine was N₁- and N₂-glucoside, whereas the other metabolites such as N-oxide, N₁- and N₂-glucuronide, and hydroxide were also observed. In monkeys and human volunteers, N₁- and N₂-glucuronide was detected as the main metabolite in urine, whereas glucosides were absent. Judging from the urinary profile of FYX-051 metabolites, a marked species difference would exist in the metabolism of FYX-051, although the urinary profile in the monkeys and human volunteers was considered to be relatively similar. The ratio of N₁- and N₂-glucuronide in monkeys was similar to that in the human volunteers (Table 2). With regard to the position of conjugation of FYX-051, the present study indicated that compared with N₂-conjugation, N₁-conjugation was more predominant. This is because in each species, the amount of N₁-conjugate was considerably higher than that of N₂-cojugate.

The present study indicates that the N-glucuronidation and N-glucosidation of FYX-051 occurred at the same position of the triazole ring, resulting in the generation of four different conjugates in mammals.

	Acknowledgments

 
We thank Dr. Yoshiaki Sato, ADME/TOX Research Institute, Daiichi Pure Chemicals Co., Ltd., for the radioisotope study, and Dr. Ken Kawaguchi, Toray Research Center Inc., for the NMR analysis. We also thank Drs. Tomomitsu Sasaki and Tsutomu Inoue, Research Laboratories 1, Fuji Yakuhin Co., Ltd., for the syntheses of reference compounds.

	Footnotes

 
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

doi:10.1124/dmd.106.011692.

ABBREVIATIONS: FYX-051, 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile; XOR, xanthine oxidoreductase; MC, methylcellulose; HPLC, high-performance liquid chromatography; LC/MS, liquid chromatography/mass spectrometry; COSY, correlation spectroscopy; NOESY, nuclear Overhauser effect spectroscopy; HSQC, heteronuclear single quantum coherence; HMBC, heteronuclear multiple bond coherence; MS/MS, tandem mass spectrometry; JNJ-10198409, 6,7-(dimethoxy-2,4-dihydroinden-[1,2-C]pyrazol-3-yl)-(3-fluoro-phenyl)-amine.

Address correspondence to: Takashi Nakazawa, Research Laboratories 2, Fuji Yakuhin Co., Ltd., 636-1 Iidashinden, Nishi-ku, Saitama 331-0068, Japan. E-mail: l2-20640{at}fujiyakuhin.co.jp

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This Article Abstract Full Text (PDF) All Versions of this Article: dmd.106.011692v1 34/11/1880    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nakazawa, T. Articles by Nagata, O. Search for Related Content PubMed PubMed Citation Articles by Nakazawa, T. Articles by Nagata, O.