Details of the Drug

General Information of Drug (ID: DMOQVU9)

Drug Name

Hydroxyurea

Synonyms

Biosupressin; Droxia; Hidrix; Hidroxicarbamida; Hydrea; Hydreia; Hydroxicarbamidum; Hydroxyaminomethanamide; Hydroxycarbamid; Hydroxycarbamide; Hydroxycarbamidum; Hydroxycarbamine; Hydroxyharnstoff; Hydroxylurea; Hydura; Hydurea; Idrossicarbamide; Litaler; Litalir; Mylocel; NHY; Oncocarbide; Oxyurea; Siklos; Carbamide oxide; Carbamohydroxamic acid; Carbamohydroximic acid; Carbamohydroxyamic acid; Carbamoyl oxime; Carbamyl hydroxamate; Carrbamoyl Oxime; Hydroxyharnstoff [German]; Idrossicarbamide [DCIT]; H 8627; SK 22591; SQ 1089; DRG-0253; Droxia (TM); Droxia (TN); HYDREA (TN); HYDROXY-UREA; Hidroxicarbamida [INN-Spanish]; Hydrea (TM); Hydroxycarbamidum [INN-Latin]; Hydroxyurea (D4); Hydroxyurea (USP); Hydroxyurea [USAN:BAN]; Hydroxyurea(d4); N-Carbamoylhydroxylamine; N-HYDROXY UREA; N-Hydroxymocovina; N-Hydroxymocovina [Czech]; N-Hydroxyurea; Onco-carbide; SQ-1089; Tetratogen: inhibits ribonucleoside diphosphate reductase; Hydroxycarbamide (JAN/INN); N-(Aminocarbonyl) Hydroxyamine; Hydrea, Biosupressin, Cytodrox, Hydroxyurea; S-phase/G-1 interface inhibitor; 1-HYDROXYUREA

Indication

Disease Entry	ICD 11	Status	REF
Chronic myelogenous leukaemia	2A20.0	Approved	[1]
Desmoid tumour	2F7C	Approved	[2]
Fibromatosis	N.A.	Approved	[2]
Head and neck cancer	2D42	Approved	[2]
Melanoma	2C30	Approved	[2]
Pulmonary hypertension	BB01	Approved	[2]
Sickle-cell anaemia	3A51	Approved	[2]
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Therapeutic Class

Anticancer Agents

Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 0

Molecular Weight (mw)

76.055

Logarithm of the Partition Coefficient (xlogp)

-1.8

Rotatable Bond Count (rotbonds)

Hydrogen Bond Donor Count (hbonddonor)

Hydrogen Bond Acceptor Count (hbondacc)

ADMET Property

Absorption: The drug is well absorbed from the gastrointestinal tract []
BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3: high solubility and low permeability [3]
Bioavailability: 79% of drug becomes completely available to its intended biological destination(s) [4]
Clearance: The drug present in the plasma can be removed from the body at the rate of 1.5 mL/min/kg [5]
Elimination: 80% of drug is excreted from urine in the unchanged form [3]
Half-life: The concentration or amount of drug in body reduced by one-half in 3 - 4 hours [5]
Metabolism: The drug is metabolized via the hepatic []
MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 1502.57324 micromolar/kg/day [6]
Unbound Fraction: The unbound fraction of drug in plasma is 1% [5]
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 0.52 L/kg [5]
Water Solubility: The ability of drug to dissolve in water is measured as 50 mg/mL [3]

Adverse Drug Reaction (ADR)

ADR Term	Variation	Related DOT	DOT ID	REF
Chronic myeloid leukaemia	Not Available	ABL1	OT09YVXH	[7]
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Chemical Identifiers

Formula: CH4N2O2
IUPAC Name: hydroxyurea
Canonical SMILES: C(=O)(N)NO
InChI: InChI=1S/CH4N2O2/c2-1(4)3-5/h5H,(H3,2,3,4)
InChIKey: VSNHCAURESNICA-UHFFFAOYSA-N

Cross-matching ID

PubChem CID: 3657
ChEBI ID: CHEBI:44423
CAS Number: 127-07-1
DrugBank ID: DB01005
TTD ID: D07CWD
VARIDT ID: DR01177
ACDINA ID: D00317

Combinatorial Drugs (CBD)

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Repurposed Drugs (RPD)

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Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Ribonucleoside-diphosphate reductase M2 (RRM2)	TTBWDI0	RIR2_HUMAN	Modulator	[8]

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Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[9]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[9]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[9]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[10]

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Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
5'-AMP-activated protein kinase subunit beta-1 (PRKAB1)	OT1OG4QZ	AAKB1_HUMAN	Gene/Protein Processing	[11]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Gene/Protein Processing	[12]
Ataxin-1 (ATXN1)	OTQF0HNR	ATX1_HUMAN	Gene/Protein Processing	[11]
Borealin (CDCA8)	OT17D55D	BOREA_HUMAN	Gene/Protein Processing	[13]
Carnitine O-palmitoyltransferase 2, mitochondrial (CPT2)	OTIN6G20	CPT2_HUMAN	Gene/Protein Processing	[11]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Gene/Protein Processing	[14]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Gene/Protein Processing	[15]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Gene/Protein Processing	[16]
Cyclin-dependent kinase 5 activator 1 (CDK5R1)	OTJELWK0	CD5R1_HUMAN	Gene/Protein Processing	[17]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Gene/Protein Processing	[12]

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Molecular Interaction Atlas (MIA)

MIA Detail

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Molecular Expression Atlas of This Drug

The Studied Disease

Chronic myelogenous leukaemia

ICD Disease Classification

2A20.0

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Ribonucleoside-diphosphate reductase M2 (RRM2)	DTT	RRM2	1.66E-04	2.66	1.68
P-glycoprotein 1 (ABCB1)	DTP	P-GP	2.74E-01	-2.19E-01	-3.03E-01
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTP	OATP1A2	2.63E-02	-2.27E-01	-1.21E+00
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DTP	OATP1B3	2.10E-05	-2.39E-02	-3.15E-02
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DTP	OATP1B1	9.07E-02	-9.94E-02	-5.12E-01

Molecular Expression Atlas (MEA)

MEA Detail

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Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Same Disease as Hydroxyurea

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Disease	REF
Omacetaxine mepesuccinate	DMPU2WX	Moderate	Additive myelosuppressive effects by the combination of Hydroxyurea and Omacetaxine mepesuccinate.	Myeloproliferative neoplasm [2A20]	[18]
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Coadministration of a Drug Treating the Disease Different from Hydroxyurea (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Roflumilast	DMPGHY8	Moderate	Additive immunosuppressive effects by the combination of Hydroxyurea and Roflumilast.	Asthma [CA23]	[19]
Ofloxacin	DM0VQN3	Minor	Decreased absorption of Hydroxyurea due to intestinal mucosa variation caused by Ofloxacin.	Bacterial infection [1A00-1C4Z]	[20]
Sparfloxacin	DMB4HCT	Minor	Decreased absorption of Hydroxyurea due to intestinal mucosa variation caused by Sparfloxacin.	Bacterial infection [1A00-1C4Z]	[20]
Gemifloxacin	DMHT34O	Minor	Decreased absorption of Hydroxyurea due to intestinal mucosa variation caused by Gemifloxacin.	Bacterial infection [1A00-1C4Z]	[20]
Norfloxacin	DMIZ6W2	Minor	Decreased absorption of Hydroxyurea due to intestinal mucosa variation caused by Norfloxacin.	Bacterial infection [1A00-1C4Z]	[20]
ABT-492	DMJFD2I	Minor	Decreased absorption of Hydroxyurea due to intestinal mucosa variation caused by ABT-492.	Bacterial infection [1A00-1C4Z]	[20]
Levofloxacin	DMS60RB	Minor	Decreased absorption of Hydroxyurea due to intestinal mucosa variation caused by Levofloxacin.	Bacterial infection [1A00-1C4Z]	[20]
Sulfinpyrazone	DMEV954	Moderate	Antagonize the effect of Hydroxyurea when combined with Sulfinpyrazone.	Gout [FA25]	[21]
Teriflunomide	DMQ2FKJ	Major	Additive myelosuppressive effects by the combination of Hydroxyurea and Teriflunomide.	Hyper-lipoproteinaemia [5C80]	[22]
Probenecid	DMMFWOJ	Moderate	Antagonize the effect of Hydroxyurea when combined with Probenecid.	Inborn purine/pyrimidine/nucleotide metabolism error [5C55]	[21]
Denosumab	DMNI0KO	Moderate	Additive myelosuppressive effects by the combination of Hydroxyurea and Denosumab.	Low bone mass disorder [FB83]	[23]
Thalidomide	DM70BU5	Major	Additive thrombogenic effects by the combination of Hydroxyurea and Thalidomide.	Multiple myeloma [2A83]	[24]
Tecfidera	DM2OVDT	Moderate	Additive immunosuppressive effects by the combination of Hydroxyurea and Tecfidera.	Multiple sclerosis [8A40]	[25]
Siponimod	DM2R86O	Major	Additive immunosuppressive effects by the combination of Hydroxyurea and Siponimod.	Multiple sclerosis [8A40]	[21]
Fingolimod	DM5JVAN	Major	Additive immunosuppressive effects by the combination of Hydroxyurea and Fingolimod.	Multiple sclerosis [8A40]	[26]
Ozanimod	DMT6AM2	Major	Additive immunosuppressive effects by the combination of Hydroxyurea and Ozanimod.	Multiple sclerosis [8A40]	[19]
Gatifloxacin	DMSL679	Minor	Decreased absorption of Hydroxyurea due to intestinal mucosa variation caused by Gatifloxacin.	Respiratory infection [CA07-CA4Z]	[20]
Canakinumab	DM8HLO5	Moderate	Additive immunosuppressive effects by the combination of Hydroxyurea and Canakinumab.	Rheumatoid arthritis [FA20]	[27]
Golimumab	DMHZV7X	Major	Additive immunosuppressive effects by the combination of Hydroxyurea and Golimumab.	Rheumatoid arthritis [FA20]	[28]
Leflunomide	DMR8ONJ	Major	Additive immunosuppressive effects by the combination of Hydroxyurea and Leflunomide.	Rheumatoid arthritis [FA20]	[22]
Anthrax vaccine	DM9GSWY	Moderate	Antagonize the effect of Hydroxyurea when combined with Anthrax vaccine.	Sepsis [1G40-1G41]	[29]
Valganciclovir	DMS2IUH	Moderate	Additive myelosuppressive effects by the combination of Hydroxyurea and Valganciclovir.	Virus infection [1A24-1D9Z]	[21]
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Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Allura red AC dye	E00338	33258	Colorant
Benzyl alcohol	E00010	244	Antimicrobial preservative; Solvent
Butylparaben	E00142	7184	Antimicrobial preservative
D&C red no. 28	E00491	6097185	Colorant
D&C red no. 33	E00261	19116	Colorant
FD&C blue no. 1	E00263	19700	Colorant
FD&C blue no. 2	E00446	2723854	Colorant
Kyselina citronova	E00014	311	Acidulant; Antioxidant; Buffering agent; Complexing agent; Flavoring agent
methylparaben	E00149	7456	Antimicrobial preservative
Propylparaben sodium	E00567	23679044	Antimicrobial preservative
Quinoline yellow WS	E00309	24671	Colorant
Sodium lauryl sulfate	E00464	3423265	Emulsifying agent; Modified-release agent; Penetration agent; Solubilizing agent; Surfactant; lubricant
Beta-D-lactose	E00099	6134	Diluent; Dry powder inhaler carrier; Lyophilization aid
Carboxymethylcellulose sodium	E00621	Not Available	Adsorbent; Binding agent; Disintegrant; Emulsifying agent; Suspending agent; Viscosity-controlling agent
Citric acid monohydrate	E00271	22230	Acidulant; Antioxidant; Buffering agent; Complexing agent; Flavoring agent
Edetate calcium disodium	E00487	6093170	Complexing agent
Eisenoxyd	E00585	56841934	Colorant
Ferrosoferric oxide	E00231	14789	Colorant
Lactose monohydrate	E00393	104938	Binding agent; Diluent; Dry powder inhaler carrier; Lyophilization aid
Magnesium stearate	E00208	11177	lubricant
Propylene glycol	E00040	1030	Antimicrobial preservative; Humectant; Plasticizing agent; Solvent
Silicon dioxide	E00670	Not Available	Anticaking agent; Opacifying agent; Viscosity-controlling agent
Sodium propionate	E00445	2723816	Antimicrobial preservative
Titanium dioxide	E00322	26042	Coating agent; Colorant; Opacifying agent
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Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Hydroxyurea 500 mg capsule	500 mg	Oral Capsule	Oral
Hydroxyurea 300 mg capsule	300 mg	Oral Capsule	Oral
Hydroxyurea 400 mg capsule	400 mg	Oral Capsule	Oral
Hydroxyurea 200 mg capsule	200 mg	Oral Capsule	Oral

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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: 6822).
2	Hydroxyurea FDA Label
3	BDDCS applied to over 900 drugs
4	Critical Evaluation of Human Oral Bioavailability for Pharmaceutical Drugs by Using Various Cheminformatics Approaches
5	Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
6	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
7	ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
8	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
9	Transcellular movement of hydroxyurea is mediated by specific solute carrier transporters. Exp Hematol. 2011 Apr;39(4):446-56.
10	Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
11	Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
12	Hydroxyurea (HU)-induced apoptosis in the mouse fetal lung. Exp Mol Pathol. 2005 Aug;79(1):59-67. doi: 10.1016/j.yexmp.2005.02.007. Epub 2005 Apr 22.
13	Characterization of DNA reactive and non-DNA reactive anticancer drugs by gene expression profiling. Mutat Res. 2007 Jun 1;619(1-2):16-29. doi: 10.1016/j.mrfmmm.2006.12.007. Epub 2007 Feb 8.
14	Dibutyryl cyclic AMP-induced enhancement of RB protein degradation in human hepatoma cells. Anticancer Res. 1999 Nov-Dec;19(6B):5181-5.
15	Senescence-like changes induced by hydroxyurea in human diploid fibroblasts. Exp Gerontol. 2000 Aug;35(5):553-71. doi: 10.1016/s0531-5565(00)00108-x.
16	The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents, IV: The mechanisms involved in inhibiting cell-cycle progression. Blood. 2001 Aug 1;98(3):842-50. doi: 10.1182/blood.v98.3.842.
17	Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
18	Product Information. Synribo (omacetaxine). Teva Pharmaceuticals USA, North Wales, PA.
19	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
20	Johnson EJ, MacGowan AP, Potter MN, et al "Reduced absorption of oral ciprofloxacin after chemotherapy for haematological malignancy." J Antimicrob Chemother 25 (1990): 837-42. [PMID: 2373666]
21	Cerner Multum, Inc. "Australian Product Information.".
22	Product Information. Arava (leflunomide). Hoechst Marion-Roussel Inc, Kansas City, MO.
23	Product Information. Prolia (denosumab). Amgen USA, Thousand Oaks, CA.
24	Bennett CL, Nebeker JR, Samore MH, et al "The Research on Adverse Drug Events and Reports (RADAR) project." JAMA 293 (2005): 2131-40. [PMID: 15870417]
25	Product Information. Vumerity (diroximel fumarate). Alkermes, Inc, Cambridge, MA.
26	Product Information. Gilenya (fingolimod). Novartis Pharmaceuticals, East Hanover, NJ.
27	Product Information. Arcalyst (rilonacept). Regeneron Pharmaceuticals Inc, Tarrytown, NY.
28	Product Information. Cimzia (certolizumab). UCB Pharma Inc, Smyrna, GA.
29	CDC. Centers for Disease Control and Prevention/ "Recommendations of the advisory committtee on immunization practices (ACIP): use of vaccines and immune globulins in persons with altered immunocompetence." MMWR Morb Mortal Wkly Rep 42(RR-04) (1993): 1-18. [PMID: 20300058]