Details of the Drug

General Information of Drug (ID: DMDKF3M)

• Drug Name: Raloxifene
• Synonyms: Raloxifene (extended-release, CDT)

Indication

Disease Entry	ICD 11	Status	REF
Osteoporosis	FB83.0	Approved	[1]

• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 1:
  Molecular Weight (mw); 473.6
  Logarithm of the Partition Coefficient (xlogp); 6.1
  Rotatable Bond Count (rotbonds); 7
  Hydrogen Bond Donor Count (hbonddonor); 2
  Hydrogen Bond Acceptor Count (hbondacc); 6
• ADMET Property:
  Absorption AUC: The area under the plot of plasma concentration (AUC) of drug is 24.2 mcgh/L []
  Absorption Cmax: The maximum plasma concentration (Cmax) of drug is 1.36 mcg/L []
  Absorption Tmax: The time to maximum plasma concentration (Tmax) is 32.5 h []
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 2: low solubility and high permeability [2]
  Clearance: The apparent oral clearance of drug is 44.1 L/h/kg []
  Elimination: 0.002% of drug is excreted from urine in the unchanged form, and 6% drug is excreted as glucuronide conjugates []
  Half-life: The concentration or amount of drug in body reduced by one-half in 27 - 32 hours [3]
  Metabolism: The drug is metabolized via the liver [3]
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 21.11506 micromolar/kg/day [4]
  Unbound Fraction: The unbound fraction of drug in plasma is 0.05% [5]
  Vd: The volume of distribution (Vd) of drug is 2348 L/kg []
  Water Solubility: The ability of drug to dissolve in water is measured as 0.013 mg/mL [2]
• Chemical Identifiers:
  Formula: C28H27NO4S
  IUPAC Name: [6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone
  Canonical SMILES: C1CCN(CC1)CCOC2=CC=C(C=C2)C(=O)C3=C(SC4=C3C=CC(=C4)O)C5=CC=C(C=C5)O
  InChI: InChI=1S/C28H27NO4S/c30-21-8-4-20(5-9-21)28-26(24-13-10-22(31)18-25(24)34-28)27(32)19-6-11-23(12-7-19)33-17-16-29-14-2-1-3-15-29/h4-13,18,30-31H,1-3,14-17H2
  InChIKey: GZUITABIAKMVPG-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 5035
  ChEBI ID: CHEBI:8772
  CAS Number: 84449-90-1
  DrugBank ID: DB00481
  TTD ID: D01XBA
  VARIDT ID: DR01347
  INTEDE ID: DR1388
  ACDINA ID: D00579

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Estrogen receptor (ESR)	TTZAYWL	ESR1_HUMAN	Modulator	[6]

Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[7]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Substrate	[8]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Substrate	[9]
UDP-glucuronosyltransferase 1A10 (UGT1A10)	DEL5N6Y	UD110_HUMAN	Substrate	[10]

Molecular Expression Atlas of This Drug

• The Studied Disease: Osteoporosis
• ICD Disease Classification: FB83.0

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
P-glycoprotein 1 (ABCB1)	DTP	P-GP	7.23E-01	-8.20E-02	-3.22E-01
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 Raloxifene (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Diazepam	DM08E9O	Minor	Increased plasma concentration of Raloxifene and Diazepam due to competitive binding of plasma proteins.	Epilepsy/seizure [8A61-8A6Z]	[11]
Diazoxide	DML1538	Minor	Increased plasma concentration of Raloxifene and Diazoxide due to competitive binding of plasma proteins.	Hypertension [BA00-BA04]	[11]
Carfilzomib	DM48K0X	Major	Additive thrombogenic effects by the combination of Raloxifene and Carfilzomib.	Multiple myeloma [2A83]	[12]

Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Mannitol	E00103	6251	Diluent; Flavoring agent; Lyophilization aid; Plasticizing agent; Tonicity agent
Sodium stearyl fumarate	E00545	23665634	lubricant
Beta-D-lactose	E00099	6134	Diluent; Dry powder inhaler carrier; Lyophilization aid
Citric acid monohydrate	E00271	22230	Acidulant; Antioxidant; Buffering agent; Complexing agent; Flavoring agent
Crospovidone	E00626	Not Available	Disintegrant
Hydroxypropyl cellulose	E00632	Not Available	Binding agent; Coating agent; Emulsifying agent; Film/Membrane-forming agent; Modified-release agent; Suspending agent; Viscosity-controlling agent
Hypromellose	E00634	Not Available	Coating agent
Lactose monohydrate	E00393	104938	Binding agent; Diluent; Dry powder inhaler carrier; Lyophilization aid
Magnesium stearate	E00208	11177	lubricant
Poloxamer 407	E00646	Not Available	Emulsifying agent; Solubilizing agent; Surfactant
Polyethylene glycol 400	E00653	Not Available	Coating agent; Diluent; Ointment base; Plasticizing agent; Solvent; Suppository base; lubricant
Polyethylene glycol 4000	E00654	Not Available	Coating agent; Diluent; Ointment base; Plasticizing agent; Solvent; Suppository base; lubricant
Polysorbate 80	E00665	Not Available	Dispersing agent; Emollient; Emulsifying agent; Plasticizing agent; Solubilizing agent; Surfactant; Suspending agent
Povidone	E00667	Not Available	Binding agent; Coating agent; Disintegrant; Film/membrane-forming agent; Solubilizing agent; Suspending agent
Propylene glycol	E00040	1030	Antimicrobial preservative; Humectant; Plasticizing agent; Solvent
Silicon dioxide	E00670	Not Available	Anticaking agent; Opacifying agent; Viscosity-controlling agent
Talc	E00520	16211421	Anticaking agent; Diluent; Glidant; lubricant
Titanium dioxide	E00322	26042	Coating agent; Colorant; Opacifying agent
Vinylpyrrolidone	E00668	Not Available	Binding agent; Coating agent; Disintegrant; Film/membrane-forming agent; Solubilizing agent; Suspending agent
Hydrophobic colloidal silica	E00285	24261	Anticaking agent; Emulsion stabilizing agent; Glidant; Suspending agent; Viscosity-controlling agent
Cellulose microcrystalline	E00698	Not Available	Adsorbent; Suspending agent; Diluent
Pregelatinized starch	E00674	Not Available	Binding agent; Diluent; Disintegrant

Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Raloxifene Hydrochloride 60mg tablet	60mg	Tablet	Oral
Raloxifene 60 mg tablet	60 mg	Oral Tablet	Oral

Jump to Detail Pharmaceutical Formulation Page of This Drug

References

• [1] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [2] BDDCS applied to over 900 drugs
• [3] Raloxifene: a selective estrogen receptor modulator. Am Fam Physician. 1999 Sep 15;60(4):1131-9.
• [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] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [6] 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. (Target id: 620).
• [7] Influence of hepatic and intestinal efflux transporters and their genetic variants on the pharmacokinetics and pharmacodynamics of raloxifene in osteoporosis treatment. Transl Res. 2012 Oct;160(4):298-308.
• [8] The role of P-glycoprotein in the bioactivation of raloxifene. Drug Metab Dispos. 2006 Dec;34(12):2073-8.
• [9] Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov;32(11):1201-8.
• [10] Characterization of raloxifene glucuronidation: potential role of UGT1A8 genotype on raloxifene metabolism in vivo. Cancer Prev Res (Phila). 2013 Jul;6(7):719-30.
• [11] Product Information. Evista (raloxifene). Lilly, Eli and Company, Indianapolis, IN.
• [12] Cerner Multum, Inc. "Australian Product Information.".