Details of the Drug

General Information of Drug (ID: DM0YZC6)

• Drug Name: Fulvestrant
• Synonyms: Faslodex; AstraZeneca brand of fulvestrant; Fulvestrant [USAN]; Ici 182780; ZD 182780; ZM 182780; Faslodex (TN); ZD-182780; ZD-9238; ZM-182780; Faslodex(ICI 182,780); Faslodex, ICI 182780, Fulvestrant; Fulvestrant (JAN/USAN/INN); (7R,13S,17S)-13-methyl-7-(9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol; (7R,8R,9S,13S,14S,17S)-13-methyl-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol; (7R,8S,9S,13S,14S,17S)-13-methyl-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl) nonyl]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol; (7alpha,17beta)-7-{9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl}estra-1,3,5(10)-triene-3,17-diol; 7-(9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl)estra-1,3,5(10)-triene-3,17-diol; 7alpha-(9-((4,4,5,5,5,-Pentafluoropentyl)sulfinyl)nonyl)estra-1,3,5(10)-triene-3,17beta-diol; 7alpha-(9-((4,4,5,5,5-Pentafluoropentyl)sulfinyl)nonyl)estra-1,3,5(10)-triene-3,17beta-diol; 7alpha-[9[(4,4,5,5,5-Pentafluropentyl)sulfinyl]nonyl]-estra-1,3,5(10)-triene-3, 17 beta diol; ICI

Indication

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[1]

• Therapeutic Class: Anticancer Agents
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 3:
  Molecular Weight (mw); 606.8
  Logarithm of the Partition Coefficient (xlogp); 9.2
  Rotatable Bond Count (rotbonds); 14
  Hydrogen Bond Donor Count (hbonddonor); 2
  Hydrogen Bond Acceptor Count (hbondacc); 9
• ADMET Property:
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 2: low solubility and high permeability [2]
  Clearance: The drug present in the plasma can be removed from the body at the rate of 11.8 mL/min/kg [3]
  Elimination: 0.1% 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 40 days [3]
  Metabolism: The drug is metabolized via the liver []
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.00023 micromolar/kg/day [4]
  Unbound Fraction: The unbound fraction of drug in plasma is 0.01% [3]
  Vd: The volume of distribution (Vd) of drug is 3-5 L/kg []
  Water Solubility: The ability of drug to dissolve in water is measured as 0.001 mg/mL [2]
• Chemical Identifiers:
  Formula: C32H47F5O3S
  IUPAC Name: (7R,8R,9S,13S,14S,17S)-13-methyl-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol
  Canonical SMILES: C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2O)[C@@H](CC4=C3C=CC(=C4)O)CCCCCCCCCS(=O)CCCC(C(F)(F)F)(F)F
  InChI: InChI=1S/C32H47F5O3S/c1-30-17-15-26-25-12-11-24(38)21-23(25)20-22(29(26)27(30)13-14-28(30)39)10-7-5-3-2-4-6-8-18-41(40)19-9-16-31(33,34)32(35,36)37/h11-12,21-22,26-29,38-39H,2-10,13-20H2,1H3/t22-,26-,27+,28+,29-,30+,41?/m1/s1
  InChIKey: VWUXBMIQPBEWFH-WCCTWKNTSA-N
• Cross-matching ID:
  PubChem CID: 104741
  ChEBI ID: CHEBI:31638
  CAS Number: 129453-61-8
  DrugBank ID: DB00947
  TTD ID: D0JO7Y
  INTEDE ID: DR0756

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Estrogen receptor (ESR)	TTZAYWL	ESR1_HUMAN	Antagonist	[5]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4) Main DME	DE4LYSA	CP3A4_HUMAN	Substrate	[6]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Substrate	[7]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
2-aminoethanethiol dioxygenase (ADO)	OTRLGQ7V	AEDO_HUMAN	Post-Translational Modifications	[8]
2-oxoglutarate dehydrogenase complex component E1 (OGDH)	OTHGTQWF	ODO1_HUMAN	Post-Translational Modifications	[8]
24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1)	OTBAJT4I	CP39A_HUMAN	Post-Translational Modifications	[8]
26S proteasome complex subunit SEM1 (SEM1)	OTASLBM1	SEM1_HUMAN	Post-Translational Modifications	[8]
26S proteasome non-ATPase regulatory subunit 14 (PSMD14)	OTJWHMZ5	PSDE_HUMAN	Gene/Protein Processing	[9]
26S proteasome non-ATPase regulatory subunit 6 (PSMD6)	OTX59EGK	PSMD6_HUMAN	Gene/Protein Processing	[9]
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1 (HSD3B1)	OTNAZVKB	3BHS1_HUMAN	Post-Translational Modifications	[8]
3',5'-cyclic-AMP phosphodiesterase 4D (PDE4D)	OT1RWFV0	PDE4D_HUMAN	Post-Translational Modifications	[8]
3-hydroxyisobutyrate dehydrogenase, mitochondrial (HIBADH)	OTCMMMIZ	3HIDH_HUMAN	Post-Translational Modifications	[8]
5-hydroxytryptamine receptor 5A (HTR5A)	OTRKPCQV	5HT5A_HUMAN	Post-Translational Modifications	[8]

Molecular Expression Atlas of This Drug

• The Studied Disease: Breast cancer
• ICD Disease Classification: 2C60-2C65

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DME	UGT1A1	7.69E-01	1.91E-02	5.45E-02
Cytochrome P450 3A4 (CYP3A4)	DME	CYP3A4	9.85E-01	2.24E-02	7.33E-02

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Fulvestrant (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Omacetaxine mepesuccinate	DMPU2WX	Moderate	Additive myelosuppressive effects by the combination of Fulvestrant and Omacetaxine mepesuccinate.	Myeloproliferative neoplasm [2A20]	[10]

References

• [1] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 1015).
• [2] BDDCS applied to over 900 drugs
• [3] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [4] 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
• [5] Beta3-tubulin is induced by estradiol in human breast carcinoma cells through an estrogen-receptor dependent pathway. Cell Motil Cytoskeleton. 2009 Jul;66(7):378-88.
• [6] Fulvestrant: pharmacologic profile versus existing endocrine agents for the treatment of breast cancer. Ann Pharmacother. 2006 Sep;40(9):1572-83.
• [7] Inactivation of the pure antiestrogen fulvestrant and other synthetic estrogen molecules by UDP-glucuronosyltransferase 1A enzymes expressed in breast tissue. Mol Pharmacol. 2006 Mar;69(3):908-20.
• [8] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [9] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [10] Product Information. Synribo (omacetaxine). Teva Pharmaceuticals USA, North Wales, PA.