Details of the Drug

General Information of Drug (ID: DMA04DE)

• Drug Name: Topiroxostat
• Synonyms: FYX-051; Xanthine oxidoreductase inhibitor (oral, gout), Fuji Yakuhin

Indication

Disease Entry	ICD 11	Status	REF
Gout	FA25	Phase 2	[1]

• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 248.24
  Topological Polar Surface Area (xlogp); 1.2
  Rotatable Bond Count (rotbonds); 2
  Hydrogen Bond Donor Count (hbonddonor); 1
  Hydrogen Bond Acceptor Count (hbondacc); 5
• ADMET Property:
  Absorption AUC: The area under the plot of plasma concentration (AUC) of drug is 1319 +/- 162 mcgh/L [2]
  Absorption Cmax: The maximum plasma concentration (Cmax) of drug is 413 +/- 77 mcg/L [2]
  Absorption Tmax: The time to maximum plasma concentration (Tmax) is 0.5-6 h [2]
  Clearance: The renal clearance of drug is 17.4 mL/h [3]
  Elimination: Urinary excretion and fecal excretion of radiolabeled topiroxostat are 30.4% and 40.9% of total dose of 1mg/kg administered to rats, respectively [4]
  Half-life: The concentration or amount of drug in body reduced by one-half in 5 hours [3]
  Metabolism: The drug is metabolized via the hepatic metabolism [5]
• Chemical Identifiers:
  Formula: C13H8N6
  IUPAC Name: 4-(5-pyridin-4-yl-1H-1,2,4-triazol-3-yl)pyridine-2-carbonitrile
  Canonical SMILES: C1=CN=CC=C1C2=NC(=NN2)C3=CC(=NC=C3)C#N
  InChI: InChI=1S/C13H8N6/c14-8-11-7-10(3-6-16-11)13-17-12(18-19-13)9-1-4-15-5-2-9/h1-7H,(H,17,18,19)
  InChIKey: UBVZQGOVTLIHLH-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 5288320
  CAS Number: 577778-58-6
  DrugBank ID: DB01685
  TTD ID: D0WK0P
  INTEDE ID: DR1619

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Xanthine dehydrogenase/oxidase (XDH)	TT7RJY8	XDH_HUMAN	Inhibitor	[6]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
UDP-glucuronosyltransferase 1A9 (UGT1A9) Main DME	DE85D2P	UD19_HUMAN	Substrate	[7]

References

• [1] ClinicalTrials.gov (NCT02327754) Effect of Topiroxostat on Urinary Albumin Excretion Early Stage Diabetic Nephropathy and Hyperuricemia With or Without Gout. U.S. National Institutes of Health.
• [2] Pharmacokinetics, metabolism and excretion of [(14)C]-lenalidomide following oral administration in healthy male subjects. Cancer Chemother Pharmacol. 2012 Mar;69(3):789-97. doi: 10.1007/s00280-011-1760-3. Epub 2011 Oct 29.
• [3] Pharmaceuticals and Medical Devices Agency (PMDA): Topiroxostat review
• [4] Nakazawa T, Miyata K, Omura K, Iwanaga T, Nagata O: 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. Drug Metab Dispos. 2006 Nov;34(11):1880-6. Epub 2006 Aug 16.
• [5] Kamdem LK, Liu Y, Stearns V, Kadlubar SA, Ramirez J, Jeter S, Shahverdi K, Ward BA, Ogburn E, Ratain MJ, Flockhart DA, Desta Z: In vitro and in vivo oxidative metabolism and glucuronidation of anastrozole. Br J Clin Pharmacol. 2010 Dec;70(6):854-69. doi: 10.1111/j.1365-2125.2010.03791.x.
• [6] QT/QTc study conducted in Japanese adult healthy subjects: a novel xanthine oxidase inhibitor topiroxostat was not associated with QT prolongation. J Clin Pharmacol. 2014 Apr;54(4):446-52.
• [7] Characterization of N-glucuronidation of 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl) pyridine-2-carbonitrile (FYX-051): a new xanthine oxidoreductase inhibitor. Drug Metab Dispos. 2007 Dec;35(12):2143-8.
• [8] Polymorphic expression of UGT1A9 is associated with variable acetaminophen glucuronidation in neonates: a population pharmacokinetic and pharmacogenetic study. Clin Pharmacokinet. 2018 Oct;57(10):1325-1336.
• [9] Glucuronidation of nonsteroidal anti-inflammatory drugs: identifying the enzymes responsible in human liver microsomes. Drug Metab Dispos. 2005 Jul;33(7):1027-35.
• [10] Pharmacokinetic interaction involving sorafenib and the calcium-channel blocker felodipine in a patient with hepatocellular carcinoma. Invest New Drugs. 2011 Dec;29(6):1511-4.
• [11] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [12] The evolution of population pharmacokinetic models to describe the enterohepatic recycling of mycophenolic acid in solid organ transplantation and autoimmune disease. Clin Pharmacokinet. 2011 Jan;50(1):1-24.
• [13] The UDP-glucuronosyltransferase 1A9 enzyme is a peroxisome proliferator-activated receptor alpha and gamma target gene. J Biol Chem. 2003 Apr 18;278(16):13975-83.
• [14] Allopurinol: xanthine oxidase inhibitor. Tex Med. 1966 Jan;62(1):100-1.
• [15] Clinical pipeline report, company report or official report of Takeda (2009).
• [16] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2021
• [17] Inhibition studies of bovine xanthine oxidase by luteolin, silibinin, quercetin, and curcumin. J Nat Prod. 2009 Apr;72(4):725-31.
• [18] Oxypurinol as an inhibitor of xanthine oxidase-catalyzed production of superoxide radical. Biochem Pharmacol. 1988 Jan 15;37(2):349-52.
• [19] Inhibition of cow's milk xanthine oxidase by flavonoids. J Nat Prod. 1988 Mar-Apr;51(2):345-8.
• [20] Clinical pipeline report, company report or official report of Teijin Pharma.
• [21] Pharmacokinetics, pharmacodynamics, and tolerability of LC350189, a novel xanthine oxidase inhibitor, in healthy subjects. Drug Des Devel Ther. 2015 Aug 31;9:5033-49.
• [22] An updated patent review: xanthine oxidase inhibitors for the treatment of hyperuricemia and gout (2011-2015).Expert Opin Ther Pat. 2017 Mar;27(3):311-345.