Details of the Drug

General Information of Drug (ID: DMCE985)

• Drug Name: Phenazone
• Synonyms: antipyrine; Phenazone; 60-80-0; Antipyrin; Phenazon; Analgesine; Anodynine; Fenazone; Anodynin; Azophen; 2,3-Dimethyl-1-phenyl-5-pyrazolone; Antipirin; Phenozone; Methozin; Azophene; Phenylone; Pyrazophyl; Sedatine; Apirelina; Sedatin; Dimethyloxychinizin; Dimethyloxyquinazine; Phenazonum; Antipyrinum; Oxydimethylquinazine; Azophenum; Parodyne; Phenylon; Fenazona; 3-Antipyrine; Fenazon [Czech]; Auralgan; Fenazon; Fenazona [INN-Spanish]; Phenazone (pharmaceutical); 3H-Pyrazol-3-one, 1,2-dihydro-1,5-dimethyl-2-phenyl-; Oxydimethylquinizine

Indication

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[1]

• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 188.23
  Topological Polar Surface Area (xlogp); 0.4
  Rotatable Bond Count (rotbonds); 1
  Hydrogen Bond Donor Count (hbonddonor); 0
  Hydrogen Bond Acceptor Count (hbondacc); 2
• ADMET Property:
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 1: high solubility and high permeability [2]
  Bioavailability: 99% of drug becomes completely available to its intended biological destination(s) [3]
  Clearance: The drug present in the plasma can be removed from the body at the rate of 0.64 mL/min/kg [4]
  Elimination: 0.5% of drug is excreted from urine in the unchanged form [2]
  Half-life: The concentration or amount of drug in body reduced by one-half in 12 hours [4]
  Unbound Fraction: The unbound fraction of drug in plasma is 0.93% [4]
  Vd: Fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma 0.77 L/kg [4]
  Water Solubility: The ability of drug to dissolve in water is measured as 1700 mg/mL [2]
• Chemical Identifiers:
  Formula: C11H12N2O
  IUPAC Name: 1,5-dimethyl-2-phenylpyrazol-3-one
  Canonical SMILES: CC1=CC(=O)N(N1C)C2=CC=CC=C2
  InChI: InChI=1S/C11H12N2O/c1-9-8-11(14)13(12(9)2)10-6-4-3-5-7-10/h3-8H,1-2H3
  InChIKey: VEQOALNAAJBPNY-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 2206
  ChEBI ID: CHEBI:31225
  CAS Number: 60-80-0
  DrugBank ID: DB01435
  TTD ID: D03IRR
  VARIDT ID: DR00941
  INTEDE ID: DR0120

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Prostaglandin G/H synthase 1 (COX-1)	TT8NGED	PGH1_HUMAN	Inhibitor	[1]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Substrate	[5]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Substrate	[6]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Substrate	[6]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Substrate	[5]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Substrate	[7]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Substrate	[6]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Substrate	[5]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Substrate	[7]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Substrate	[5]
Cytochrome P450 2C18 (CYP2C18)	DEZMWRE	CP2CI_HUMAN	Substrate	[5]
RNA cytidine acetyltransferase (hALP)	DEZV4AP	NAT10_HUMAN	Substrate	[8]

Molecular Expression Atlas of This Drug

• The Studied Disease: Discovery agent
• ICD Disease Classification: N.A.

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Prostaglandin G/H synthase 1 (COX-1)	DTT	PTGS1	3.97E-03	0.16	0.43
RNA cytidine acetyltransferase (hALP)	DME	NAT10	8.46E-03	-4.02E-02	-2.28E-01
Cytochrome P450 2C18 (CYP2C18)	DME	CYP2C18	5.67E-02	2.96E-03	1.50E-02
Cytochrome P450 2E1 (CYP2E1)	DME	CYP2E1	1.87E-04	-1.20E-01	-3.22E-01
Cytochrome P450 2C8 (CYP2C8)	DME	CYP2C8	1.82E-04	-1.35E-01	-5.84E-01
Cytochrome P450 2B6 (CYP2B6)	DME	CYP2B6	4.88E-01	-1.69E-05	-1.28E-04
Cytochrome P450 2A6 (CYP2A6)	DME	CYP2A6	2.02E-01	-2.49E-02	-1.81E-01
Cytochrome P450 1A2 (CYP1A2)	DME	CYP1A2	7.36E-01	1.62E-02	1.08E-01
Mephenytoin 4-hydroxylase (CYP2C19)	DME	CYP2C19	2.40E-01	-3.31E-02	-1.97E-01
Cytochrome P450 2D6 (CYP2D6)	DME	CYP2D6	7.30E-01	-1.91E-02	-1.41E-01
Cytochrome P450 2C9 (CYP2C9)	DME	CYP2C9	1.90E-01	-9.81E-03	-5.96E-02
Cytochrome P450 3A4 (CYP3A4)	DME	CYP3A4	1.04E-02	6.29E-02	3.54E-01

References

• [1] Pharmacokinetic and pharmacodynamic aspects of the ideal COX-2 inhibitor: a pharmacologist's perspective. Clin Exp Rheumatol. 2001 Nov-Dec;19(6 Suppl 25):S51-7.
• [2] BDDCS applied to over 900 drugs
• [3] Critical Evaluation of Human Oral Bioavailability for Pharmaceutical Drugs by Using Various Cheminformatics Approaches
• [4] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [5] 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.
• [6] Identification of the human hepatic cytochromes P450 involved in the in vitro oxidation of antipyrine. Drug Metab Dispos. 1996 Apr;24(4):487-94.
• [7] Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metab Dispos. 1997 Mar;25(3):390-3.
• [8] Evaluation of the influence of diabetes mellitus on antipyrine metabolism and CYP1A2 and CYP2D6 activity. Pharmacotherapy. 2000 Feb;20(2):182-90.
• [9] Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer. 2007 Mar 1;109(5):957-65.
• [10] Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
• [11] Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
• [12] Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
• [13] Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
• [14] Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
• [15] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [16] The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1994 Jul 19;48(2):267-76.
• [17] Roles of cytochromes P450 1A2, 2A6, and 2C8 in 5-fluorouracil formation from tegafur, an anticancer prodrug, in human liver microsomes. Drug Metab Dispos. 2000 Dec;28(12):1457-63.
• [18] Effects of polyunsaturated fatty acids on prostaglandin synthesis and cyclooxygenase-mediated DNA adduct formation by heterocyclic aromatic amines in human adenocarcinoma colon cells. Mol Carcinog. 2004 Jul;40(3):180-8.
• [19] Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1). Drug Metab Dispos. 2014 Nov;42(11):1843-50.
• [20] Cytochrome P450 1A2 (CYP1A2) activity and risk factors for breast cancer: a cross-sectional study. Breast Cancer Res. 2004;6(4):R352-65.
• [21] PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genomics. 2015 Aug;25(8):416-26.
• [22] The effect of apigenin on pharmacokinetics of imatinib and its metabolite N-desmethyl imatinib in rats. Biomed Res Int. 2013;2013:789184.
• [23] The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentrations in Chinese coke oven workers. Sci Total Environ. 2007 Aug 1;381(1-3):38-46.
• [24] Identification of P450 enzymes involved in metabolism of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1993 Sep;348(3):332-7.
• [25] Metabolism and metabolic inhibition of xanthotoxol in human liver microsomes. Evid Based Complement Alternat Med. 2016;2016:5416509.
• [26] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [27] Genotoxicity of tamoxifen, tamoxifen epoxide and toremifene in human lymphoblastoid cells containing human cytochrome P450s. Carcinogenesis. 1994 Jan;15(1):5-9.
• [28] Psychotropic drug interactions with valproate. Clin Neuropharmacol. 2005 Mar-Apr;28(2):96-101.
• [29] The role of human cytochrome P450 enzymes in the formation of 2-hydroxymetronidazole: CYP2A6 is the high affinity (low Km) catalyst. Drug Metab Dispos. 2013 Sep;41(9):1686-94.
• [30] Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol. Br J Anaesth. 1998 Jun;80(6):788-95.
• [31] CYP2A6- and CYP2A13-catalyzed metabolism of the nicotine delta-5'(1')iminium ion. J Pharmacol Exp Ther. 2012 Nov;343(2):307-15.
• [32] Arylamine N-acetyltransferase in human red blood cells. Biochem Pharmacol. 1992 Sep 25;44(6):1099-104.
• [33] A population and family study of N-acetyltransferase using caffeine urinary metabolites. Clin Pharmacol Ther. 1993 Aug;54(2):134-41.
• [34] Effect of H2-receptor antagonists on rat liver cytosolic acetyl CoA:arylamine N-acetyltransferase activity. Drug Metab Dispos. 1992 Jan-Feb;20(1):74-8.
• [35] Crystallization and preliminary X-ray characterization of arylamine N-acetyltransferase C (BanatC) from Bacillus anthracis. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2007 Oct 1;63(Pt 10):862-4.
• [36] Identification of cytochrome P450 and arylamine N-acetyltransferase isoforms involved in sulfadiazine metabolism. Drug Metab Dispos. 2005 Jul;33(7):969-76.
• [37] Genetic analysis of bacterial acetyltransferases: identification of amino acids determining the specificities of the aminoglycoside 6'-N-acetyltransferase Ib and IIa proteins. J Bacteriol. 1992 May;174(10):3196-203.
• [38] NAT1 genotypes do not predict response to mesalamine in patients with ulcerative colitis. Z Gastroenterol. 2008 Mar;46(3):259-65.
• [39] Xanthine oxidase inhibition by allopurinol affects the reliability of urinary caffeine metabolic ratios as markers for N-acetyltransferase 2 and CYP1A2 activities. Eur J Clin Pharmacol. 1999 Jan;54(11):869-76.
• [40] Aminoglycoside resistance resulting from tight drug binding to an altered aminoglycoside acetyltransferase. Antimicrob Agents Chemother. 2003 May;47(5):1577-83.
• [41] Effect of common NAT2 variant alleles in the acetylation of the major clonazepam metabolite, 7-aminoclonazepam. Drug Metab Lett. 2007 Jan;1(1):3-5.
• [42] Inhibitory effects of anticancer drugs on dextromethorphan-O-demethylase activity in human liver microsomes. Cancer Chemother Pharmacol. 1993;32(6):491-5.
• [43] Effect of genetic polymorphism on the metabolism of endogenous neuroactive substances, progesterone and p-tyramine, catalyzed by CYP2D6. Brain Res Mol Brain Res. 2004 Oct 22;129(1-2):117-23.
• [44] CYP2D6 polymorphisms and tamoxifen metabolism: clinical relevance. Curr Oncol Rep. 2010 Jan;12(1):7-15.
• [45] Inhibition of cytochrome P450 2D6: structure-activity studies using a series of quinidine and quinine analogues. Chem Res Toxicol. 2003 Apr;16(4):450-9.
• [46] Effects of propofol on human hepatic microsomal cytochrome P450 activities. Xenobiotica. 1998 Sep;28(9):845-53.
• [47] Pharmacogenetics of schizophrenia. Am J Med Genet. 2000 Spring;97(1):98-106.
• [48] Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes. Arch Toxicol. 1999 Mar;73(2):65-70.
• [49] Structure-activity relationship for human cytochrome P450 substrates and inhibitors. Drug Metab Rev. 2002 Feb-May;34(1-2):69-82.
• [50] Chronic ethanol feeding and folate deficiency activate hepatic endoplasmic reticulum stress pathway in micropigs. Am J Physiol Gastrointest Liver Physiol. 2005 Jul;289(1):G54-63.
• [51] Cytochrome P450 2E1 null mice provide novel protection against cisplatin-induced nephrotoxicity and apoptosis. Kidney Int. 2003 May;63(5):1687-96.
• [52] Acetaminophen induced acute liver failure via oxidative stress and JNK activation: protective role of taurine by the suppression of cytochrome P450 2E1. Free Radic Res. 2010 Mar;44(3):340-55.
• [53] A study on the metabolism of etoposide and possible interactions with antitumor or supporting agents by human liver microsomes. J Pharmacol Exp Ther. 1998 Sep;286(3):1294-300.
• [54] Novel metabolic pathway of estrone and 17beta-estradiol catalyzed by cytochrome P-450. Drug Metab Dispos. 2000 Feb;28(2):110-2.
• [55] Inhibition of cytochrome P450 2E1 by propofol in human and porcine liver microsomes. Biochem Pharmacol. 2002 Oct 1;64(7):1151-6.
• [56] CYP2E1 and clinical features in alcoholics. Neuropsychobiology. 2003;47(2):86-9.
• [57] Diclofenac and its derivatives as tools for studying human cytochromes P450 active sites: particular efficiency and regioselectivity of P450 2Cs. Biochemistry. 1999 Oct 26;38(43):14264-70.
• [58] Identification of human cytochrome P450s involved in the formation of all-trans-retinoic acid principal metabolites. Mol Pharmacol. 2000 Dec;58(6):1341-8.
• [59] Targeted antipeptide antibodies to cytochrome P450 2C18 based on epitope mapping of an inhibitory monoclonal antibody to P450 2C51. Arch Biochem Biophys. 1997 Feb 15;338(2):157-64.
• [60] Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes. Chem Res Toxicol. 1996 Mar;9(2):365-73.
• [61] CYP2C8/9 mediate dapsone N-hydroxylation at clinical concentrations of dapsone. Drug Metab Dispos. 2000 Aug;28(8):865-8.
• [62] Induction of CYP2C genes in human hepatocytes in primary culture. Drug Metab Dispos. 2001 Mar;29(3):242-51.
• [63] Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016 Jan;68(1):168-241.
• [64] Differential expression and function of CYP2C isoforms in human intestine and liver. Pharmacogenetics. 2003 Sep;13(9):565-75.
• [65] Analysis of human cytochrome P450 2C8 substrate specificity using a substrate pharmacophore and site-directed mutants. Biochemistry. 2004 Dec 14;43(49):15379-92.
• [66] Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Nov;68(5):1111-8.
• [67] PharmGKB summary: mycophenolic acid pathway. Pharmacogenet Genomics. 2014 Jan;24(1):73-9.
• [68] Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and 3A4 in human liver microsomes. Arch Biochem Biophys. 1997 Oct 1;346(1):161-9.
• [69] Tamoxifen inhibits cytochrome P450 2C9 activity in breast cancer patients. J Chemother. 2006 Aug;18(4):421-4.
• [70] Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology. 2003 Aug;144(8):3382-98.
• [71] Drug-drug interactions with imatinib: an observational study. Medicine (Baltimore). 2016 Oct;95(40):e5076.
• [72] Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A. Drug Metab Dispos. 2000 Feb;28(2):125-30.
• [73] New insights into the structural features and functional relevance of human cytochrome P450 2C9. Part I. Curr Drug Metab. 2009 Dec;10(10):1075-126.
• [74] A potential role for the estrogen-metabolizing cytochrome P450 enzymes in human breast carcinogenesis. Breast Cancer Res Treat. 2003 Dec;82(3):191-7.
• [75] A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother. 1998 May;32(5):554-63.
• [76] Effect of tamoxifen on the enzymatic activity of human cytochrome CYP2B6. J Pharmacol Exp Ther. 2002 Jun;301(3):945-52.
• [77] Hepatic metabolism of diclofenac: role of human CYP in the minor oxidative pathways. Biochem Pharmacol. 1999 Sep 1;58(5):787-96.
• [78] Insights into CYP2B6-mediated drug-drug interactions. Acta Pharm Sin B. 2016 Sep;6(5):413-425.
• [79] Drugs that may have potential CYP2B6 interactions.
• [80] Involvement of human cytochrome P450 2B6 in the omega- and 4-hydroxylation of the anesthetic agent propofol. Xenobiotica. 2007 Jul;37(7):717-24.
• [81] Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-butanone metabolism by cytochrome P450 2B6. Drug Metab Dispos. 2005 Dec;33(12):1760-4.
• [82] PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012 Jun;22(6):466-70.
• [83] Application of the relative activity factor approach in scaling from heterologously expressed cytochromes p450 to human liver microsomes: studies on amitriptyline as a model substrate. J Pharmacol Exp Ther. 2001 Apr;297(1):326-37.
• [84] High-dose rabeprazole/amoxicillin therapy as the second-line regimen after failure to eradicate H. pylori by triple therapy with the usual doses of a proton pump inhibitor, clarithromycin and amoxicillin. Hepatogastroenterology. 2003 Nov-Dec;50(54):2274-8.
• [85] Cytochrome P450 pharmacogenetics and cancer. Oncogene. 2006 Mar 13;25(11):1679-91.
• [86] CYP2C19*17 is associated with decreased breast cancer risk. Breast Cancer Res Treat. 2009 May;115(2):391-6.
• [87] Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1995 Dec;353(1):116-21.
• [88] Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001 Feb;120(2):525-33.
• [89] The C50T polymorphism of the cyclooxygenase-1 gene and the risk of thrombotic events during low-dose therapy with acetyl salicylic acid. Thromb Haemost. 2008 Jul;100(1):70-5.
• [90] Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers. J Clin Pharmacol. 2000 Oct;40(10):1109-20.
• [91] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [92] Cox-2 inhibitory effects of naturally occurring and modified fatty acids. J Nat Prod. 2001 Jun;64(6):745-9.
• [93] Comparison of cyclooxygenase inhibitory activity and ocular anti-inflammatory effects of ketorolac tromethamine and bromfenac sodium. Curr Med Res Opin. 2006 Jun;22(6):1133-40.
• [94] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [95] Ouellet M, Percival MD: Effect of inhibitor time-dependency on selectivity towards cyclooxygenase isoforms. Biochem J. 1995 Feb 15;306 ( Pt 1):247-51.
• [96] Differential binding mode of diverse cyclooxygenase inhibitors. J Mol Graph Model. 2002 Mar;20(5):359-71.
• [97] Differential metabolism of dihomo-gamma-linolenic acid and arachidonic acid by cyclo-oxygenase-1 and cyclo-oxygenase-2: implications for cellular synthesis of prostaglandin E1 and prostaglandin E2. Biochem J. 2002 Jul 15;365(Pt 2):489-96.