HYDROXYCHLOROQUINE

Details

Stereochemistry	RACEMIC
Molecular Formula	C18H26ClN3O
Molecular Weight	335.8722
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCN(CCCC(C)Nc1ccnc2cc(ccc12)Cl)CCO

InChI

InChIKey=XXSMGPRMXLTPCZ-UHFFFAOYSA-N

InChI=1S/C18H26ClN3O/c1-3-22(11-12-23)10-4-5-14(2)21-17-8-9-20-18-13-15(19)6-7-16(17)18/h6-9,13-14,23H,3-5,10-12H2,1-2H3,(H,20,21)

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB01611
Curator's Comment:: Description was created based on several sources, including http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/009768s041lbl.pdf

Hydroxychloroquine possesses antimalarial properties and also exerts a beneficial effect in lupus erythematosus (chronic discoid or systemic) and acute or chronic rheumatoid arthritis. Although the exact mechanism of action is unknown, it may be based on ability of hydroxychloroquine to bind to and alter DNA. Hydroxychloroquine has also has been found to be taken up into the acidic food vacuoles of the parasite in the erythrocyte. This increases the pH of the acid vesicles, interfering with vesicle functions and possibly inhibiting phospholipid metabolism. In suppressive treatment, hydroxychloroquine inhibits the erythrocytic stage of development of plasmodia. In acute attacks of malaria, it interrupts erythrocytic schizogony of the parasite. Its ability to concentrate in parasitized erythrocytes may account for their selective toxicity against the erythrocytic stages of plasmodial infection. As an antirheumatic, hydroxychloroquine is thought to act as a mild immunosuppressant, inhibiting the production of rheumatoid factor and acute phase reactants. It also accumulates in white blood cells, stabilizing lysosomal membranes and inhibiting the activity of many enzymes, including collagenase and the proteases that cause cartilage breakdown. Hydroxychloroquine is used for the suppressive treatment and treatment of acute attacks of malaria due to Plasmodium vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. It is also indicated for the treatment of discoid and systemic lupus erythematosus, and rheumatoid arthritis.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Toll-like receptor 7 12 Target ID: CHEMBL5936 Sources: http://www.drugbank.ca/drugs/DB01611	Antagonist 2575		2.78 µM [IC50]
Toll-like receptor 9 4 Target ID: CHEMBL5804 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24342772	Antagonist 2575		0.08 µM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Malaria 89 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/009768s041lbl.pdf	Curative	Approved 8043	PLAQUENIL Approved Use PLAQUENIL is indicated for the suppressive treatment and treatment of acute attacks of malaria due to Plasmodium vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. It is also indicated for the treatment of discoid and systemic lupus erythematosus, and rheumatoid arthritis. Launch Date -4.64227205E11
Systemic lupus erythematosus 16 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/009768s041lbl.pdf	Primary	Approved 8043	PLAQUENIL Approved Use PLAQUENIL is indicated for the suppressive treatment and treatment of acute attacks of malaria due to Plasmodium vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. It is also indicated for the treatment of discoid and systemic lupus erythematosus, and rheumatoid arthritis. Launch Date -4.64227205E11
Rheumatoid arthritis 294 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/009768s041lbl.pdf	Primary	Approved 8043	PLAQUENIL Approved Use PLAQUENIL is indicated for the suppressive treatment and treatment of acute attacks of malaria due to Plasmodium vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. It is also indicated for the treatment of discoid and systemic lupus erythematosus, and rheumatoid arthritis. Launch Date -4.64227205E11

C_max

Value	Dose	Analyte	Population
129.6 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/009768Orig1s051lbl.pdf	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	HYDROXYCHLOROQUINE SULFATE blood	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
1.22 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19188392	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered:	HYDROXYCHLOROQUINE SULFATE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
50.3 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/009768Orig1s051lbl.pdf	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	HYDROXYCHLOROQUINE SULFATE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
102.3 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19188392	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered:		HYDROXYCHLOROQUINE SULFATE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
537 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/009768Orig1s051lbl.pdf	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	HYDROXYCHLOROQUINE SULFATE blood	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
172.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19188392	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered:	HYDROXYCHLOROQUINE SULFATE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
2963 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/009768Orig1s051lbl.pdf	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	HYDROXYCHLOROQUINE SULFATE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
48% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8359187	unknown, unknown		HYDROXYCHLOROQUINE SULFATE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
12 g 1 times / day single, oral Studied dose Dose: 12 g, 1 times / day Route: oral Route: single Dose: 12 g, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/11555803/	healthy, 16 years n = 1 Health Status: healthy Age Group: 16 years Sex: M Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/11555803/	Other AEs: Cardio-respiratory arrest... Other AEs: Cardio-respiratory arrest (grade 5) Sources: https://pubmed.ncbi.nlm.nih.gov/11555803/
200 mg 1 times / day single, oral Studied dose Dose: 200 mg, 1 times / day Route: oral Route: single Dose: 200 mg, 1 times / day Co-administed with:: levothyroxine aspirin ibuprofen Sources: https://pubmed.ncbi.nlm.nih.gov/11555803/	healthy, 16 years n = 1 Health Status: healthy Age Group: 16 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/11555803/	Other AEs: Tachycardia, Hypotension... Other AEs: Tachycardia Hypotension Depression Hypokalemia Sources: https://pubmed.ncbi.nlm.nih.gov/11555803/
20 g 1 times / day single, oral Studied dose Dose: 20 g, 1 times / day Route: oral Route: single Dose: 20 g, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/11555803/	healthy, 18 years n = 1 Health Status: healthy Age Group: 18 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/11555803/	Other AEs: Hypotension, Hypokalemia... Other AEs: Hypotension Hypokalemia Sources: https://pubmed.ncbi.nlm.nih.gov/11555803/
12 g 1 times / day single, oral Studied dose Dose: 12 g, 1 times / day Route: oral Route: single Dose: 12 g, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/11555803/	healthy, 2.5 years n = 1 Health Status: healthy Age Group: 2.5 years Sex: M Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/11555803/	Other AEs: Cardio-respiratory arrest... Other AEs: Cardio-respiratory arrest (grade 5) Sources: https://pubmed.ncbi.nlm.nih.gov/11555803/
4 g 1 times / day single, oral Studied dose Dose: 4 g, 1 times / day Route: oral Route: single Dose: 4 g, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/11555803/	healthy, 29 years n = 1 Health Status: healthy Age Group: 29 years Sex: M Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/11555803/	Other AEs: Vomiting, Ventricular tachycardia... Other AEs: Vomiting Ventricular tachycardia Sources: https://pubmed.ncbi.nlm.nih.gov/11555803/
600 mg 2 times / day multiple, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Co-administed with:: temozolomide(150 mg/m2; daily for 7/14 d) Sources: https://pubmed.ncbi.nlm.nih.gov/24991839/	unhealthy, median age 64 years n = 8 Health Status: unhealthy Condition: advanced solid malignancies Age Group: median age 64 years Sex: M+F Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/24991839/	DLT: Nausea, Vomiting... Other AEs: Lymphopenia, Anemia... Dose limiting toxicities: Nausea (grade 3, 13%) Vomiting (grade 3, 13%) Other AEs: Lymphopenia (grade 3-4, 13%) Anemia (grade 1-2, 13%) Thrombocytopenia (grade 1-2, 13%) Anorexia (grade 1-2, 38%) Bradycardia (grade 1-2, 13%) Constipation (grade 1-2, 25%) Diarrhea (grade 1-2, 25%) Fatigue (grade 1-2, 88%) Hypotension (grade 1-2, 13%) Nausea (grade 1-2, 50%) Rash (grade 1-2, 13%) Vomiting (grade 1-2, 25%) Sources: https://pubmed.ncbi.nlm.nih.gov/24991839/
200 mg 2 times / day multiple, oral Studied dose Dose: 200 mg, 2 times / day Route: oral Route: multiple Dose: 200 mg, 2 times / day Co-administed with:: temozolomide(150 mg/m2; daily for 7/14 d) Sources: https://pubmed.ncbi.nlm.nih.gov/24991839/	unhealthy, median age 64 years n = 15 Health Status: unhealthy Condition: advanced solid malignancies Age Group: median age 64 years Sex: M+F Population Size: 15 Sources: https://pubmed.ncbi.nlm.nih.gov/24991839/	DLT: Heart block... Dose limiting toxicities: Heart block (grade 3, 6.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/24991839/
500 mg 2 times / day multiple, oral Studied dose Dose: 500 mg, 2 times / day Route: oral Route: multiple Dose: 500 mg, 2 times / day Co-administed with:: temozolomide(150 mg/m2; daily for 7/14 d) Sources: https://pubmed.ncbi.nlm.nih.gov/24991839/	unhealthy, median age 64 years n = 7 Health Status: unhealthy Condition: advanced solid malignancies Age Group: median age 64 years Sex: M+F Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/24991839/	DLT: Rash... Dose limiting toxicities: Rash (grade 3, 14.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/24991839/
200 mg 2 times / day steady, oral Dose: 200 mg, 2 times / day Route: oral Route: steady Dose: 200 mg, 2 times / day Sources: https://clinicaltrials.gov/ct2/show/NCT01537315	unhealthy n = 7 Health Status: unhealthy Condition: cardiovascular disease Population Size: 7 Sources: https://clinicaltrials.gov/ct2/show/NCT01537315	Other AEs: Increased blood pressure... Other AEs: Increased blood pressure (below serious, 1 patient) Sources: https://clinicaltrials.gov/ct2/show/NCT01537315

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1601		substrate 1118 inhibitor 1702	inhibitor 1475

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP2C8 634 CYP3A5 367

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP2D6 1738	inhibitor 3045 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2015042/	yes		yes (co-administration study) Comment: Concomitant administration of HCQ increased the bioavailability of metoprolol, as indicated by significant increases in the area under the plasma concentration-time curve (65 ± 4.6%) and maximal plasma concentrations (72 ± 6.9%) of metoprolol Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2015042/

Drug as victim

Target	Modality	Activity
CYP2C8 634	substrate 3113 Sources: https://onlinelibrary.wiley.com/doi/full/10.1002/art.39402; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600351/	likely
CYP2D6 1118	substrate 3113 Sources: https://onlinelibrary.wiley.com/doi/full/10.1002/art.39402; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600351/	likely
CYP3A4 1601	substrate 3113 Sources: https://onlinelibrary.wiley.com/doi/full/10.1002/art.39402; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600351/	likely
CYP3A5 367	substrate 3113 Sources: https://onlinelibrary.wiley.com/doi/full/10.1002/art.39402; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600351/	likely

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1507	inhibitor 1489 Sources: https://pubmed.ncbi.nlm.nih.gov/33674391/

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:5801	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:5801
ChemicalBook	CB6866802	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB6866802
MolPort	MolPort-003-847-792	https://www.molport.com/shop/molecule-link/MolPort-003-847-792
eMolecules	901965	https://www.emolecules.com/cgi-bin/more?vid=901965

PubMed

Title	Date	PubMed
Hydroxychloroquine-induced vertigo.	1975 Sep 1	1173923
Antimalarial drugs in systemic lupus erythematosus: use in pregnancy.	2001	11735661
[Amphiphilic cationic drug myopathy, drug-induced lysosomal storage lipidosis].	2001	11596386
Management of hepatitis C virus-related arthritis.	2001	11580301
Combination therapy with disease modifying anti-rheumatic drugs in rheumatoid arthritis.	2001	11543695
Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study.	2001	11434574
Antimalarials--the 'real' advance in lupus.	2001	11434570
Treatment of rheumatoid arthritis: unknown long-term effects.	2001 Apr	11718162
Leflunomide and rheumatoid arthritis: new preparation. Neither the safest nor the most effective slow-acting antirheumatic drug.	2001 Apr	11718154
Pilot tolerability studies of hydroxychloroquine and colchicine in Alzheimer disease.	2001 Apr-Jun	11403336
Early hydroxychloroquine macular toxicity.	2001 Aug	11508449
Bromocriptine in rheumatic and autoimmune diseases.	2001 Aug	11503136
Effect of hydroxychloroquine on progression of dementia in early Alzheimer's disease: an 18-month randomised, double-blind, placebo-controlled study.	2001 Aug 11	11513909
Systemic lupus erythematosus: current management.	2001 Aug 6	11548075
Angiooedema due to acquired deficiency of C1-esterase inhibitor associated with leucocytoclastic vasculitis.	2001 Aug-Sep	11720182
[Combined basic therapeutic drugs. From individual hope to targeted use].	2001 Dec	11826745
Progress in the treatment of rheumatoid arthritis.	2001 Dec 12	11735734
Fatal toxic epidermal necrolysis associated with hydroxychloroquine.	2001 Jul	11488840
Hydroxychloroquine enhances the endocrine secretion of adenovirus-directed growth hormone from rat submandibular glands in vivo.	2001 Jul 1	11440626
Treating early rheumatoid arthritis in the younger patient.	2001 Jun	11409156
Conventional DMARD options for patients with a suboptimal response to methotrexate.	2001 Jun	11409154
Disease modifying antirheumatic drugs: longterm safety issues.	2001 Jun	11409152
Rheumatologists' attitudes toward routine screening for hydroxychloroquine retinopathy.	2001 Jun	11409112
[Lymphedema of the upper limb, a complication of rheumatoid polyarthritis].	2001 Jun 30	11484403
[Photodermatosis induced by hydroxychloroquine: 4 cases].	2001 Jun-Jul	11460035
Hydroxychloroquine sulphate inhibits in vitro apoptosis of circulating lymphocytes in patients with systemic lupus erythematosus.	2001 Mar	11495297
Vitamin D levels in women with systemic lupus erythematosus and fibromyalgia.	2001 Nov	11708429
Dermatomyositis.	2001 Nov 1	11730311
[Psychiatric manifestations of lupus erythematosus systemic and Sjogren's syndrome].	2001 Nov-Dec	11865567
Modulation of hormones in the treatment of lupus.	2001 Oct	11680780
Treatment of early seropositive rheumatoid arthritis: a two-year, double-blind comparison of minocycline and hydroxychloroquine.	2001 Oct	11665963
Leflunomide for the treatment of systemic lupus erythematosus: comment on the article by McMurray.	2001 Oct	11642648
Treatment of hydroxychloroquine overdose.	2001 Sep	11555803
Ocular toxicity and antenatal exposure to chloroquine or hydroxychloroquine for rheumatic diseases.	2001 Sep 8	11564493
Safety and efficacy of disease-modifying anti-rheumatic agents: focus on the benefits and risks of etanercept.	2002	11945114
Sustained normalization of cerebral blood-flow after iloprost therapy in a patient with neuropsychiatric systemic lupus erythematosus.	2002	11898921
Evidence of transplacental passage of hydroxychloroquine in humans.	2002 Apr	11953993
Delay to institution of therapy and induction of remission using single-drug or combination-disease-modifying antirheumatic drug therapy in early rheumatoid arthritis.	2002 Apr	11953964
Canadian Consensus Conference on hydroxychloroquine.	2002 Apr	11950041
Randomized double blind trial of an extract from the pentacyclic alkaloid-chemotype of uncaria tomentosa for the treatment of rheumatoid arthritis.	2002 Apr	11950006
Pharmacoeconomics of long-term treatment of rheumatoid arthritis.	2002 Apr	11934345
[Primary Gougerot-Sjögren syndrome in a 13-year-old girl].	2002 Feb	11915495
Prescribing trends in disease modifying antirheumatic drugs for rheumatoid arthritis: a survey of practicing Canadian rheumatologists.	2002 Feb	11838842
Antimalarial agents in pregnancy.	2002 Feb 9	11853823
Second-line drugs used in recent-onset rheumatoid arthritis in Brittany (France).	2002 Jan	11858354
Treatment of severe immune thrombocytopenia associated with systemic lupus erythematosus: 59 cases.	2002 Jan	11824975
Leflunomide induced fevers, thrombocytosis, and leukocytosis in a patient with relapsing polychondritis.	2002 Jan	11824960
IgM antibodies against cytomegalovirus in SLE nephritis: viral infection or aspecific autoantibody?	2002 Jan-Feb	11936434
Hydroxychloroquine reverses platelet activation induced by human IgG antiphospholipid antibodies.	2002 Mar	11916085
The effectiveness of hydroxychloroquine in patients with type 2 diabetes mellitus who are refractory to sulfonylureas--a randomized trial.	2002 Mar	11850097

Patents

Sample Use Guides

In Vivo Use Guide

Malaria: Suppression— In adults, 400 mg (=310 mg base) on exactly the same day of each week. In infants and children, the weekly suppressive dosage is 5 mg, calculated as base, per kg of body weight, but should not exceed the adult dose regardless of weight.

Route of Administration: Oral

In Vitro Use Guide

After 48 hours of stimulation with PMA and ionomycin, Hydroxychloroquine (25-100 uM) inhibited the production of IL-6, IL-17 and IL-22 in the PBMCs of healthy volunteers

Name

Type

Language

HYDROXYCHLOROQUINE

Official Name

English

HYDROXYCHLOROQUINE [INN]

Common Name

English

HYDROXYCHLOROQUINE [WHO-DD]

Common Name

English

HYDROXYCHLOROQUINE [MI]

Common Name

English

(+/-)-2-((4-((7-CHLORO-4-QUINOLYL)AMINO)PENTYL)ETHYLAMINO)ETHANOL

Systematic Name

English

HYDROXYCHLOROQUINE [VANDF]

Common Name

English

POLIRREUMIN

Brand Name

English

ETHANOL, 2-((4-((7-CHLORO-4-QUINOLINYL)AMINO)PENTYL)ETHYL)AMINO-, (+/-)-

Systematic Name

English

Classification Tree Code System Code

EU-Orphan Drug

EU/3/16/1820