Hydroxyurea

Details

Stereochemistry	ACHIRAL
Molecular Formula	CH4N2O2
Molecular Weight	76.0547
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC(=O)NO

InChI

InChIKey=VSNHCAURESNICA-UHFFFAOYSA-N

InChI=1S/CH4N2O2/c2-1(4)3-5/h5H,(H3,2,3,4)

HIDE SMILES / InChI

Description
Sources: https://www.pdr.net/drug-summary/Hydrea-hydroxyurea-888 | https://www.ncbi.nlm.nih.gov/pubmed/24839362

Hydroxyurea is an oral antimetabolite; inhibits ribonucleotide reductase and DNA synthesis. It is used for resistant chronic myeloid leukemia, locally advanced squamous cell carcinomas of the head and neck (excluding lip) in combination with concurrent chemoradiation, and to reduce the frequency of painful crises and the need for blood transfusions in patients with sickle cell anemia with recurrent moderate to severe painful crises. Hydroxyurea, a myelosuppressive agent, is the only effective drug proven to reduce the frequency of painful episodes. It raises the level of HbF and the haemoglobin level. It usually decreases the rate of painful episodes by 50%. It was first tested in sickle cell disease in 1984. It also decreases the rate of ACS episodes and blood transfusions by ~50 % in adults. It was developed as an anticancer drug and has been used to treat myeloproliferative syndromes-leukemia, melanoma, and ovarian cancer. It was approved for use by FDA in adults. Side effects includes neutropenia, bone marrow suppression, elevation of hepatic enzymes, anorexia, nausea, vomiting and infertility.

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Ribonucleotide reductase 8 Target ID: CHEMBL3301398 Sources: https://www.ncbi.nlm.nih.gov/pubmed/1641648 \| https://www.ncbi.nlm.nih.gov/pubmed/18367739	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Sickle cell anemia 12 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/016295s049s050lbl.pdf	Primary		Approved 8429	DROXIA Approved Use DROXIA is an antimetabolite indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in patients with sickle cell anemia with recurrent moderate to severe painful crises Launch Date 1967

C_max

Value	Dose	Co-administered	Analyte	Population
793.75 μM EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/9473217	2000 mg single, oral dose: 2000 mg route of administration: Oral experiment type: SINGLE co-administered:		HYDROXYUREA plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
3934 μM × h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/9473217	2000 mg single, oral dose: 2000 mg route of administration: Oral experiment type: SINGLE co-administered:		HYDROXYUREA plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
3.32 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/9473217	2000 mg single, oral dose: 2000 mg route of administration: Oral experiment type: SINGLE co-administered:		HYDROXYUREA plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
40 mg/kg 2 times / day single, oral Highest studied dose Dose: 40 mg/kg, 2 times / day Route: oral Route: single Dose: 40 mg/kg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17439737	unhealthy, 2-18 years n = 10 Health Status: unhealthy Condition: allogeneic transplantation Age Group: 2-18 years Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/17439737	Sources: https://pubmed.ncbi.nlm.nih.gov/17439737
26.7 mg/kg 1 times / day multiple, oral MTD Dose: 26.7 mg/kg, 1 times / day Route: oral Route: multiple Dose: 26.7 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/32472611/	unhealthy, 2-18 years Health Status: unhealthy Condition: sickle cell anemia Age Group: 2-18 years Sources: https://pubmed.ncbi.nlm.nih.gov/32472611/	Sources: https://pubmed.ncbi.nlm.nih.gov/32472611/
20 mg/kg 1 times / day multiple, oral Recommended Dose: 20 mg/kg, 1 times / day Route: oral Route: multiple Dose: 20 mg/kg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208843s000lbl.pdf	unhealthy, 2-18 years Health Status: unhealthy Age Group: 2-18 years Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208843s000lbl.pdf	Other AEs: Myelosuppression... Other AEs: Myelosuppression Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208843s000lbl.pdf
20 mg/kg 1 times / day steady, oral Dose: 20 mg/kg, 1 times / day Route: oral Route: steady Dose: 20 mg/kg, 1 times / day Sources: https://clinicaltrials.gov/ct2/show/NCT01976416	unhealthy n = 104 Health Status: unhealthy Condition: Malaria Population Size: 104 Sources: https://clinicaltrials.gov/ct2/show/NCT01976416	Other AEs: Sudden death, Thrombocytopenia... Other AEs: Sudden death (serious, 1 patient) Thrombocytopenia (below serious, 11 patient) Sources: https://clinicaltrials.gov/ct2/show/NCT01976416

AEs

AE	Significance	Dose	Population
Myelosuppression		20 mg/kg 1 times / day multiple, oral Recommended Dose: 20 mg/kg, 1 times / day Route: oral Route: multiple Dose: 20 mg/kg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208843s000lbl.pdf	unhealthy, 2-18 years Health Status: unhealthy Age Group: 2-18 years Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208843s000lbl.pdf
Thrombocytopenia	below serious, 11 patient	20 mg/kg 1 times / day steady, oral Dose: 20 mg/kg, 1 times / day Route: oral Route: steady Dose: 20 mg/kg, 1 times / day Sources: https://clinicaltrials.gov/ct2/show/NCT01976416	unhealthy n = 104 Health Status: unhealthy Condition: Malaria Population Size: 104 Sources: https://clinicaltrials.gov/ct2/show/NCT01976416
Sudden death	serious, 1 patient	20 mg/kg 1 times / day steady, oral Dose: 20 mg/kg, 1 times / day Route: oral Route: steady Dose: 20 mg/kg, 1 times / day Sources: https://clinicaltrials.gov/ct2/show/NCT01976416	unhealthy n = 104 Health Status: unhealthy Condition: Malaria Population Size: 104 Sources: https://clinicaltrials.gov/ct2/show/NCT01976416

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461 BCRP 699 OATP1B1 788 OATP1B3 706 BSEP 402 MRP2 383 MRP3 157 MRP4 204 CYP1A2 1524 CYP2A6 707 CYP2C19 1478 CYP2E1 882	OATP1B3 350 OATP1A2 62 OATP1B1 406 OCTN1 47 OCTN2 50 CYP 270	P-gp 257

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP2D6 1891	inhibitor 3277 Sources: https://bioinformatics.charite.de/transformer/index.php?site=fullinfo&cname=000127071, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1978168/, https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkwyODkiLCJ1c2VfY3VzdG9tX3F1ZXJ5Ijp0cnVlLCJzZWFyY2hfdGVybSI6IiIsInRleHRfZmlsdGVyIjoiQ0hFTUJMNDY3In19	likely [IC50 >10 uM]	yes (pharmacogenomic study) Comment: Of the 73 children completing the study, 42 had reduced-functioning alleles; 82% of the 27 children taking hydoxyurea had reduced-functioning alleles, versus 47% of 36 those with mild disease (P < .05). Sources: https://bioinformatics.charite.de/transformer/index.php?site=fullinfo&cname=000127071, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1978168/, https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkwyODkiLCJ1c2VfY3VzdG9tX3F1ZXJ5Ijp0cnVlLCJzZWFyY2hfdGVybSI6IiIsInRleHRfZmlsdGVyIjoiQ0hFTUJMNDY3In19
CYP3A4 1925	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/17180388/, https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkwzNDAiLCJ1c2VfY3VzdG9tX3F1ZXJ5Ijp0cnVlLCJzZWFyY2hfdGVybSI6IiIsInRleHRfZmlsdGVyIjoiQ0hFTUJMNDY3In19	no [Activation 39.8107 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkwzMzU2IiwidXNlX2N1c3RvbV9xdWVyeSI6dHJ1ZSwic2VhcmNoX3Rlcm0iOiIiLCJ0ZXh0X2ZpbHRlciI6IkNIRU1CTDQ2NyJ9fQ%3D%3D	no [IC50 >10 uM]
CYP2A6 739	inhibitor 3277 Sources: https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkw1MjgyIiwidXNlX2N1c3RvbV9xdWVyeSI6dHJ1ZSwic2VhcmNoX3Rlcm0iOiIiLCJ0ZXh0X2ZpbHRlciI6IkNIRU1CTDQ2NyJ9fQ%3D%3D	no [IC50 >10 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkwzNjIyIiwidXNlX2N1c3RvbV9xdWVyeSI6dHJ1ZSwic2VhcmNoX3Rlcm0iOiIiLCJ0ZXh0X2ZpbHRlciI6IkNIRU1CTDQ2NyJ9fQ%3D%3D	no [IC50 >10 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkwzMzk3IiwidXNlX2N1c3RvbV9xdWVyeSI6dHJ1ZSwic2VhcmNoX3Rlcm0iOiIiLCJ0ZXh0X2ZpbHRlciI6IkNIRU1CTDQ2NyJ9fQ%3D%3D	no [IC50 >10 uM]
CYP2E1 970	inhibitor 3277 Sources: https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkw1MjgxIiwidXNlX2N1c3RvbV9xdWVyeSI6dHJ1ZSwic2VhcmNoX3Rlcm0iOiIiLCJ0ZXh0X2ZpbHRlciI6IkNIRU1CTDQ2NyJ9fQ%3D%3D	no [IC50 >10 uM]
BSEP 403	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/23956101/	no [IC50 >133 uM]
MRP2 475	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/23956101/	no [IC50 >133 uM]
MRP3 207	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/23956101/	no [IC50 >133 uM]
MRP4 238	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/23956101/	no [IC50 >133 uM]
BCRP 773	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/17180388/	no
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/17180388/	no
OATP1B1 803	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/23571415/	yes
OATP1B3 715	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/23571415/	yes
P-gp 1650	inducer 1573 Sources: https://bioinformatics.charite.de/transformer/index.php?site=fullinfo&cname=000127071, https://pubmed.ncbi.nlm.nih.gov/1550597/	yes

Drug as victim

Target	Modality	Activity
CYP 270	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/19817872/	no
OATP1A2 62	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/21256917/	weak
OATP1B1 406	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/21256917/	weak
OCTN1 47	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/21256917/	weak
OCTN2 50	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/21256917/	weak
OATP1B3 350	substrate 3367 Sources: https://bioinformatics.charite.de/transformer/index.php?site=fullinfo&cname=000127071, https://pubmed.ncbi.nlm.nih.gov/21256917/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkwyNDAiLCJ1c2VfY3VzdG9tX3F1ZXJ5Ijp0cnVlLCJzZWFyY2hfdGVybSI6IiIsInRleHRfZmlsdGVyIjoiQ0hFTUJMNDY3In19

PubMed

Title	Date	PubMed
In vivo and in vitro comparison of the short-term hematopoietic toxicity between hydroxyurea and trimidox or didox, novel ribonucleotide reductase inhibitors with potential anti-HIV-1 activity.	1999	10606163
Hydroxyurea inhibits intracellular Toxoplasma gondii multiplication.	2000 Apr 1	10731610
Pure red cell aplasia in a patient with chronic granulocytic leukaemia treated with interferon-alpha.	2000 Feb	10762306
Hydroxyurea-induced cutaneous ulceration in older patients.	2000 Feb	10682958
Excess peripheral neuropathy in patients treated with hydroxyurea plus didanosine and stavudine for HIV infection.	2000 Feb 18	10716516
A case of bilateral heel ulcers associated with hydroxyurea therapy for chronic myelogenous leukemia.	2000 Mar	10798544
Systematic review of combination antiretroviral therapy with didanosine plus hydroxyurea: a partial solution to Africa's HIV/AIDS problem?	2001	11285159
Stroke prevention and treatment in sickle cell disease.	2001 Apr	11295986
Chromosomal aberrations in lymphocytes of employees in transformer and generator production exposed to electromagnetic fields and mineral oil.	2001 Apr	11255210
The anti-malarial artesunate is also active against cancer.	2001 Apr	11251172
A new molecular role for iron in regulation of cell cycling and differentiation of HL-60 human leukemia cells: iron is required for transcription of p21(WAF1/CIP1) in cells induced by phorbol myristate acetate.	2001 Apr	11241357
Role of petasin in the potential anti-inflammatory activity of a plant extract of petasites hybridus.	2001 Apr 15	11286996
Replication and G2 checkpoints: their response to caffeine.	2001 Feb	11289610
Induction of unscheduled DNA synthesis in hairless mouse epidermis by 8-methoxypsoralen plus ultraviolet A (PUVA).	2001 Feb	11255790
A compromised yeast RNA polymerase II enhances UV sensitivity in the absence of global genome nucleotide excision repair.	2001 Feb	11254132
Coupling of Saccharomyces cerevisiae early meiotic gene expression to DNA replication depends upon RPD3 and SIN3.	2001 Feb	11156977
Dynamics of seminal plasma HIV-1 decline after antiretroviral treatment.	2001 Feb 16	11273229
Chronic neutrophilic leukemia (CNL): a clinical, pathologic and cytogenetic study.	2001 Jan	11243396
Current management in polycythemia vera.	2001 Jan	11242599
Inhibition of hepatitis B virus production associated with high levels of intracellular viral DNA intermediates in iron-depleted HepG2.2.15 cells.	2001 Jan	11211885
N-(Hydroxyaminocarbonyl)phenylalanine: a novel class of inhibitor for carboxypeptidase A.	2001 Jan	11197339
Drug Points: pancreatitis associated with hydroxyurea in combination with didanosine.	2001 Jan 13	11154621
Reduction of telomerase activity in human liver cancer cells by a histone deacetylase inhibitor.	2001 Jun	11319763
Management of patients with essential thrombocythemia: current concepts and perspectives.	2001 Mar	11317966
Hydrogenosome morphological variation induced by fibronectin and other drugs in Trichomonas vaginalis and Tritrichomonas foetus.	2001 Mar	11293569
Localised chronic eyedlid disease resulting from long term hydroxyurea therapy.	2001 Mar	11277103
The Saccharomyces cerevisiae MUM2 gene interacts with the DNA replication machinery and is required for meiotic levels of double strand breaks.	2001 Mar	11238403
Topoisomerase IV, alone, unknots DNA in E. coli.	2001 Mar 15	11274059
The BARD1-CstF-50 interaction links mRNA 3' end formation to DNA damage and tumor suppression.	2001 Mar 9	11257228
Body composition in women with sickle cell disease.	2001 Winter	11289248

Patents

Sample Use Guides

In Vivo Use Guide

Usual Adult Dose for Chronic Myelogenous Leukemia 15 mg/kg/day orally as a single dose Usual Adult Dose for Head and Neck Cancer 15 mg/kg/day orally as a single dose Usual Adult Dose for Sickle Cell Anemia 15 mg/kg orally once a day; increase 5 mg/kg/day every 12 weeks Maximum dose: 35 mg/kg/day Usual Pediatric Dose for Sickle Cell Anemia 2 years and older: 20 mg/kg orally once a day; increase 5 mg/kg/day every 8 weeks or if a painful crisis occurs; increase dosing only if blood counts are in the acceptable range; do not increase dosing if myelosuppression occurs; if blood counts are considered toxic, discontinue therapy until hematologic recovery Duration of therapy: Give until mild myelosuppression (absolute neutrophil count 2000/microliter to 4000/microliter) is achieved, up to 35 mg/kg/day Maximum dose: 35 mg/kg/day

Route of Administration: Oral

Name

Type

Language

Hydroxyurea

Official Name

English

HYDROXYUREA [HSDB]

Common Name

English

SIKLOS

Brand Name

English

Hydroxycarbamide [WHO-DD]

Common Name

English

SQ 1089

Code

English

HYDREA

Brand Name

English

HYDROXYCARBAMIDE [EMA EPAR]

Common Name

English

HYDROXYCARBAMIDE

Official Name

English

HYDROXYUREA [VANDF]

Common Name

English

SQ-1089

Code

English

UREA, HYDROXY-

Systematic Name

English

hydroxycarbamide [INN]

Common Name

English

HYDROXYUREA [IARC]

Common Name

English

HYDROXYUREA [USP-RS]

Common Name

English

HYDROXYUREA [USP MONOGRAPH]

Common Name

English

DROXIA

Brand Name

English

HYDROXYCARBAMIDE [EP MONOGRAPH]

Common Name

English

HYDROXYCARBAMIDE [JAN]

Common Name

English

NSC-32065

Code

English

HYDROXYUREA [MI]

Common Name

English

HYDROXYUREA [ORANGE BOOK]

Common Name

English

HYDROXYUREA [USAN]

Common Name

English

HYDROXYCARBAMIDE [MART.]

Common Name

English

Classification Tree Code System Code

WHO-ESSENTIAL MEDICINES LIST

8.2