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Identification
NameAtovaquone
Accession NumberDB01117  (APRD00805)
Typesmall molecule
Groupsapproved
Description

A hydroxynaphthoquinone that has antimicrobial activity and is being used in antimalarial protocols. [PubChem]

Structure
Thumb
SynonymsNot Available
SaltsNot Available
Brand names
NameCompany
Malarone PediatricNot Available
MEPRONNot Available
Brand mixtures
Brand NameIngredients
MalaroneAtovaquone + Proguanil Hydrochloride
Malarone PediatricAtovaquone + Proguanil Hydrochloride
CategoriesNot Available
CAS number95233-18-4
WeightAverage: 366.837
Monoisotopic: 366.102272181
Chemical FormulaC22H19ClO3
InChI KeyKUCQYCKVKVOKAY-CTYIDZIISA-N
InChI
InChI=1S/C22H19ClO3/c23-16-11-9-14(10-12-16)13-5-7-15(8-6-13)19-20(24)17-3-1-2-4-18(17)21(25)22(19)26/h1-4,9-13,15,26H,5-8H2/t13-,15-
IUPAC Name
2-hydroxy-3-[(1r,4r)-4-(4-chlorophenyl)cyclohexyl]-1,4-dihydronaphthalene-1,4-dione
SMILES
OC1=C([C@H]2CC[C@@H](CC2)C2=CC=C(Cl)C=C2)C(=O)C2=CC=CC=C2C1=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassAcenes and Derivatives
SubclassNaphthalenes
Direct parentNaphthoquinones
Alternative parentsp-Quinones; p-Benzoquinones; Chlorobenzenes; Aryl Chlorides; Enols; Polyamines; Organochlorides
Substituentsp-benzoquinone; quinone; p-quinone; chlorobenzene; aryl halide; benzene; aryl chloride; ketone; enol; polyamine; organochloride; carbonyl group; organohalogen
Classification descriptionThis compound belongs to the naphthoquinones. These are compounds containing a naphthohydroquinone moiety, which consists of a benzene ring fused to a bezene-1,4-dione (quinone).
Pharmacology
IndicationFor the treatment or prevention of Pneumocystis carinii pneumonia in patients who are intolerant to trimethoprim-sulfamethoxazole (TMP-SMX). Also indicated for the acute oral treatment of mild to moderate PCP in patients who are intolerant to TMP-SMX.
PharmacodynamicsAtovaquone is a highly lipophilic drug that closely resembles the structure ubiquinone. Its inhibitory effect being comparable to ubiquinone, in sensitive parasites atovaquone can act by selectively affecting mitochondrial electron transport and parallel processes such as ATP and pyrimidine biosynthesis. For illustration, cytochrome bc1 complex (complex III) seems to serve as a highly discriminating molecular target for atovaquone in Plasmodia atovaquone has the advantage of not causing myelosuppression, which is an important issue in patients who have undergone bone marrow transplantation.
Mechanism of actionAtovaquone is a hydroxy- 1, 4- naphthoquinone, an analog of ubiquinone, with antipneumocystis activity. The mechanism of action against Pneumocystis carinii has not been fully elucidated. In Plasmodium species, the site of action appears to be the cytochrome bc1 complex (Complex III). Several metabolic enzymes are linked to the mitochondrial electron transport chain via ubiquinone. Inhibition of electron transport by atovaquone will result in indirect inhibition of these enzymes. The ultimate metabolic effects of such blockade may include inhibition of nucleic acid and ATP synthesis. Atovaquone also has been shown to have good in vitro activity against Toxoplasma gondii.
AbsorptionThe bioavailability of atovaquone is low and variable and is highly dependent on formulation and diet. Bioavailability of the suspension increases two-fold when administered with meals. When administered with food, bioavailability is approximately 47%. Without food, the bioavailability is 23%.
Volume of distribution
  • 0.60 ± 0.17 L/kg
Protein bindingAtovaquone is extensively bound to plasma proteins (99.9%) over the concentration range of 1 to 90 µg/mL.
Metabolism

Some evidence suggests limited metabolism (although no metabolites have been identified).

Route of eliminationThe half-life of atovaquone is long due to presumed enterohepatic cycling and eventual fecal elimination. There was little or no excretion of atovaquone in the urine (less than 0.6%).
Half life2.2 to 3.2 days
Clearance
  • 10.4 +/- 5.5 ml/min [HIV-infected patients receiving IV administration]
ToxicityThe median lethal dose is higher than the maximum oral dose tested in mice and rats (1825 mg/kg per day). Overdoses up to 31,500 mg of atovaquone have been reported. In one such patient who also took an unspecified dose of dapsone, methemoglobinemia occurred. Rash has also been reported after overdose.
Affected organisms
  • Plasmodium
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.5625
Caco-2 permeable + 0.6239
P-glycoprotein substrate Substrate 0.536
P-glycoprotein inhibitor I Non-inhibitor 0.693
P-glycoprotein inhibitor II Non-inhibitor 0.7554
Renal organic cation transporter Non-inhibitor 0.7999
CYP450 2C9 substrate Non-substrate 0.7986
CYP450 2D6 substrate Non-substrate 0.9117
CYP450 3A4 substrate Non-substrate 0.5294
CYP450 1A2 substrate Inhibitor 0.9108
CYP450 2C9 substrate Inhibitor 0.8949
CYP450 2D6 substrate Non-inhibitor 0.9231
CYP450 2C19 substrate Non-inhibitor 0.9026
CYP450 3A4 substrate Non-inhibitor 0.8309
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5773
Ames test Non AMES toxic 0.577
Carcinogenicity Non-carcinogens 0.9067
Biodegradation Not ready biodegradable 0.9922
Rat acute toxicity 2.8010 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8511
hERG inhibition (predictor II) Non-inhibitor 0.8037
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
SuspensionOral
Prices
Unit descriptionCostUnit
Malarone 250-100 mg tablet7.7USDtablet
Mepron 750 mg/5 ml suspension4.95USDml
Malarone 62.5-25 mg tablet4.33USDtablet
Mepron 150 mg/ml Suspension2.89USDml
Malarone 62.5-25 mg ped tablet2.72USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States59984491994-05-252014-05-25
Canada21502342005-03-222013-11-25
Canada21526152001-10-162013-12-23
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubilityPractically insolubleNot Available
logP5.8Not Available
Predicted Properties
PropertyValueSource
water solubility7.96e-04 g/lALOGPS
logP4.74ALOGPS
logP5ChemAxon
logS-5.7ALOGPS
pKa (strongest acidic)8.23ChemAxon
pKa (strongest basic)-4.1ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count1ChemAxon
polar surface area54.37ChemAxon
rotatable bond count2ChemAxon
refractivity103.11ChemAxon
polarizability39.55ChemAxon
number of rings4ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

DrugSyn.org

US5053432
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00236
PubChem Compound74989
PubChem Substance46507298
ChemSpider67544
BindingDB16301
ChEBI575568
ChEMBLCHEMBL1450
Therapeutic Targets DatabaseDAP000156
PharmGKBPA448502
Drug Product Database2217422
RxListhttp://www.rxlist.com/cgi/generic/atovaqu.htm
Drugs.comhttp://www.drugs.com/cdi/atovaquone.html
WikipediaAtovaquone
ATC CodesP01AX06
AHFS Codes
  • 08:30.92
PDB EntriesNot Available
FDA labelshow(63 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
RifabutinRifabutin decreases the effect of atovaquone
RifampicinRifampin may decrease the effect of atovaquone.
TetracyclineTetracycline may decrease the effect of atovaquone.
ZidovudineAtovaquone increases the effect and toxicity of zidovudine
Food Interactions
  • Fatty foods increase absorption.
  • Take with food, bioavailability is increased 2 to 3 fold.

Targets

1. Cytochrome b

Kind: protein

Organism: Plasmodium falciparum

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome b Q02768 Details

References:

  1. Winter RW, Kelly JX, Smilkstein MJ, Dodean R, Hinrichs D, Riscoe MK: Antimalarial quinolones: synthesis, potency, and mechanistic studies. Exp Parasitol. 2008 Apr;118(4):487-97. Epub 2007 Nov 7. Pubmed
  2. Cushion MT, Collins M, Hazra B, Kaneshiro ES: Effects of atovaquone and diospyrin-based drugs on the cellular ATP of Pneumocystis carinii f. sp. carinii. Antimicrob Agents Chemother. 2000 Mar;44(3):713-9. Pubmed
  3. Kaneshiro ES: Are cytochrome b gene mutations the only cause of atovaquone resistance in Pneumocystis? Drug Resist Updat. 2001 Oct;4(5):322-9. Pubmed
  4. Srivastava IK, Morrisey JM, Darrouzet E, Daldal F, Vaidya AB: Resistance mutations reveal the atovaquone-binding domain of cytochrome b in malaria parasites. Mol Microbiol. 1999 Aug;33(4):704-11. Pubmed
  5. Syafruddin D, Siregar JE, Marzuki S: Mutations in the cytochrome b gene of Plasmodium berghei conferring resistance to atovaquone. Mol Biochem Parasitol. 1999 Nov 30;104(2):185-94. Pubmed
  6. McFadden DC, Tomavo S, Berry EA, Boothroyd JC: Characterization of cytochrome b from Toxoplasma gondii and Q(o) domain mutations as a mechanism of atovaquone-resistance. Mol Biochem Parasitol. 2000 Apr 30;108(1):1-12. Pubmed
  7. Kazanjian P, Armstrong W, Hossler PA, Lee CH, Huang L, Beard CB, Carter J, Crane L, Duchin J, Burman W, Richardson J, Meshnick SR: Pneumocystis carinii cytochrome b mutations are associated with atovaquone exposure in patients with AIDS. J Infect Dis. 2001 Mar 1;183(5):819-22. Epub 2001 Feb 1. Pubmed
  8. Kessl JJ, Lange BB, Merbitz-Zahradnik T, Zwicker K, Hill P, Meunier B, Palsdottir H, Hunte C, Meshnick S, Trumpower BL: Molecular basis for atovaquone binding to the cytochrome bc1 complex. J Biol Chem. 2003 Aug 15;278(33):31312-8. Epub 2003 Jun 5. Pubmed
  9. Kessl JJ, Ha KH, Merritt AK, Lange BB, Hill P, Meunier B, Meshnick SR, Trumpower BL: Cytochrome b mutations that modify the ubiquinol-binding pocket of the cytochrome bc1 complex and confer anti-malarial drug resistance in Saccharomyces cerevisiae. J Biol Chem. 2005 Apr 29;280(17):17142-8. Epub 2005 Feb 17. Pubmed
  10. Meshnick SR, Berry EA, Nett J, Kazanjian P, Trumpower B: The interaction of atovaquone with the P. carinii cytochrome bc1 complex. J Eukaryot Microbiol. 2001;Suppl:169S-171S. Pubmed

2. Dihydroorotate dehydrogenase (quinone), mitochondrial

Kind: protein

Organism: Plasmodium falciparum (isolate 3D7)

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Dihydroorotate dehydrogenase (quinone), mitochondrial Q08210 Details

References:

  1. Cushion MT, Collins M, Hazra B, Kaneshiro ES: Effects of atovaquone and diospyrin-based drugs on the cellular ATP of Pneumocystis carinii f. sp. carinii. Antimicrob Agents Chemother. 2000 Mar;44(3):713-9. Pubmed
  2. Ittarat I, Asawamahasakda W, Bartlett MS, Smith JW, Meshnick SR: Effects of atovaquone and other inhibitors on Pneumocystis carinii dihydroorotate dehydrogenase. Antimicrob Agents Chemother. 1995 Feb;39(2):325-8. Pubmed
  3. Seymour KK, Lyons SD, Phillips L, Rieckmann KH, Christopherson RI: Cytotoxic effects of inhibitors of de novo pyrimidine biosynthesis upon Plasmodium falciparum. Biochemistry. 1994 May 3;33(17):5268-74. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

3. Dihydroorotate dehydrogenase (quinone), mitochondrial

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Dihydroorotate dehydrogenase (quinone), mitochondrial Q02127 Details

References:

  1. Knecht W, Henseling J, Loffler M: Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid. Chem Biol Interact. 2000 Jan 3;124(1):61-76. Pubmed
  2. Hansen M, Le Nours J, Johansson E, Antal T, Ullrich A, Loffler M, Larsen S: Inhibitor binding in a class 2 dihydroorotate dehydrogenase causes variations in the membrane-associated N-terminal domain. Protein Sci. 2004 Apr;13(4):1031-42. Pubmed
  3. Ittarat I, Asawamahasakda W, Bartlett MS, Smith JW, Meshnick SR: Effects of atovaquone and other inhibitors on Pneumocystis carinii dihydroorotate dehydrogenase. Antimicrob Agents Chemother. 1995 Feb;39(2):325-8. Pubmed
  4. Seymour KK, Lyons SD, Phillips L, Rieckmann KH, Christopherson RI: Cytotoxic effects of inhibitors of de novo pyrimidine biosynthesis upon Plasmodium falciparum. Biochemistry. 1994 May 3;33(17):5268-74. Pubmed
  5. Seymour KK, Yeo AE, Rieckmann KH, Christopherson RI: dCTP levels are maintained in Plasmodium falciparum subjected to pyrimidine deficiency or excess. Ann Trop Med Parasitol. 1997 Sep;91(6):603-9. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes

1. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on October 08, 2013 14:22