Details of the Drug

General Information of Drug (ID: DMY6EAO)

• Drug Name: Rosiglitazone
• Synonyms: Rosigilitazone; Rosiglitazone [INN:BAN]; Rosiglitazone maleate; Rosiglizole; TDZ 01; YASAKCUCGLMORW-UHFFFAOYSA-N; Avandamet; Avandaryl; Avandia; rosiglitazona; rosiglitazone; rosiglitazone (Avandia); rosiglitazonum; 122320-73-4; 5-((4-(2-Methyl-2-(pyridinylamino)ethoxy)phenyl)methyl)-2,4-thiazolidinedione-2-butenedioate; 5-(4-(2-(Methyl(pyridin-2-yl)amino)ethoxy)benzyl)thiazolidine-2,4-dione; 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione; BRL49653; Brl 49653; Brl-49653; C18H19N3O3S; CHEBI:50122

Indication

Disease Entry	ICD 11	Status	REF
Type-2 diabetes	5A11	Approved	[1]

• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 357.4
  Topological Polar Surface Area (xlogp); 3.1
  Rotatable Bond Count (rotbonds); 7
  Hydrogen Bond Donor Count (hbonddonor); 1
  Hydrogen Bond Acceptor Count (hbondacc); 6
• 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 0.65 mL/min/kg [4]
  Elimination: 0% 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 3.9 hours [4]
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.3721 micromolar/kg/day [5]
  Unbound Fraction: The unbound fraction of drug in plasma is 0.002% [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 0.2 L/kg [4]
  Water Solubility: The ability of drug to dissolve in water is measured as 0.04 mg/mL [2]
• Chemical Identifiers:
  Formula: C18H19N3O3S
  IUPAC Name: 5-[[4-[2-[methyl(pyridin-2-yl)amino]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione
  Canonical SMILES: CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC=CC=N3
  InChI: YASAKCUCGLMORW-UHFFFAOYSA-N
  InChIKey: 1S/C18H19N3O3S/c1-21(16-4-2-3-9-19-16)10-11-24-14-7-5-13(6-8-14)12-15-17(22)20-18(23)25-15/h2-9,15H,10-12H2,1H3,(H,20,22,23)
• Cross-matching ID:
  PubChem CID: 77999
  ChEBI ID: CHEBI:50122
  CAS Number: 122320-73-4
  DrugBank ID: DB00412
  INTEDE ID: DR1444

Molecular Interaction Atlas of This Drug

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Substrate	[6]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Substrate	[7]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Substrate	[7]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Substrate	[8]

References

• [1] Rosiglitazone was approved by FDA. The 2020 official website of the U.S. Food and Drug Administration.
• [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] Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
• [6] Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone. Clin Pharmacol Ther. 2005 May;77(5):404-14.
• [7] Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. Br J Clin Pharmacol. 1999 Sep;48(3):424-32.
• [8] 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.
• [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] Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016 Jan;68(1):168-241.
• [19] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [20] Differential expression and function of CYP2C isoforms in human intestine and liver. Pharmacogenetics. 2003 Sep;13(9):565-75.
• [21] Analysis of human cytochrome P450 2C8 substrate specificity using a substrate pharmacophore and site-directed mutants. Biochemistry. 2004 Dec 14;43(49):15379-92.
• [22] 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.
• [23] PharmGKB summary: mycophenolic acid pathway. Pharmacogenet Genomics. 2014 Jan;24(1):73-9.
• [24] Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol. Br J Anaesth. 1998 Jun;80(6):788-95.
• [25] 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.
• [26] Tamoxifen inhibits cytochrome P450 2C9 activity in breast cancer patients. J Chemother. 2006 Aug;18(4):421-4.
• [27] 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.
• [28] Drug-drug interactions with imatinib: an observational study. Medicine (Baltimore). 2016 Oct;95(40):e5076.
• [29] Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A. Drug Metab Dispos. 2000 Feb;28(2):125-30.
• [30] 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.
• [31] A potential role for the estrogen-metabolizing cytochrome P450 enzymes in human breast carcinogenesis. Breast Cancer Res Treat. 2003 Dec;82(3):191-7.
• [32] A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother. 1998 May;32(5):554-63.
• [33] Peroxidative free radical formation and O-demethylation of etoposide(VP-16) and teniposide(VM-26). Biochem Biophys Res Commun. 1986 Feb 26;135(1):215-20.