You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
Identification
NameAtovaquone
Accession NumberDB01117  (APRD00805)
TypeSmall Molecule
GroupsApproved
DescriptionA hydroxynaphthoquinone that has antimicrobial activity and is being used in antimalarial protocols. [PubChem]
Structure
Thumb
Synonyms
2-(trans-4-(P-Chlorophenyl)cyclohexyl)-3-hydroxy-1,4-naphthoquinone
Acuvel
Mepron
Wellvone
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AtovaquoneSuspension750 mg/5mLOralPrasco Laboratories2014-03-20Not applicableUs
MepronSuspension750 mg/5mLOralCardinal Health1998-09-18Not applicableUs
MepronSuspension750 mg/5mLOralGlaxo Smith Kline Llc1998-09-18Not applicableUs
MepronSuspension750 mg/5mLOralGlaxo Smith Kline Llc1995-02-28Not applicableUs
MepronSuspension750 mgOralGlaxosmithkline Inc1996-09-10Not applicableCanada
Mepron Tab 250mgTablet250 mgOralGlaxo Wellcome Inc.1993-12-311999-08-24Canada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AtovaquoneSuspension750 mg/5mLOralAmneal Pharmaceuticals of New York, LLC2011-12-09Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixtures
NameLabellerIngredients
Atovaquone and Proguanil HClPd Rx Pharmaceuticals, Inc.
Atovaquone and Proguanil HydrochlorideMylan Pharmaceuticals Inc.
Atovaquone and Proguanil Hydrochloride PediatricGlenmark Pharmaceuticals Inc.,Usa
Atovaquone ProguanilSanis Health Inc
MalaronePd Rx Pharmaceuticals, Inc.
Malarone PediatricGlaxosmithkline Inc
Mylan-atovaquone/proguanilMylan Pharmaceuticals Ulc
Teva-atovaquone ProguanilTeva Canada Limited
SaltsNot Available
Categories
UNIIY883P1Z2LT
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([[email protected]]2CC[C@@H](CC2)C2=CC=C(Cl)C=C2)C(=O)C2=CC=CC=C2C1=O
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.
Structured Indications
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.
TargetKindPharmacological actionActionsOrganismUniProt ID
Cytochrome bProteinyes
inhibitor
Plasmodium falciparumQ02768 details
Dihydroorotate dehydrogenase (quinone), mitochondrialProteinyes
inhibitor
Plasmodium falciparum (isolate 3D7)Q08210 details
Dihydroorotate dehydrogenase (quinone), mitochondrialProteinunknown
inhibitor
HumanQ02127 details
Related Articles
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
Interactions
Drug Interactions
DrugInteractionDrug group
AcepromazineThe serum concentration of Acepromazine can be increased when it is combined with Atovaquone.Approved, Vet Approved
AceprometazineThe serum concentration of Aceprometazine can be increased when it is combined with Atovaquone.Approved
AlimemazineThe serum concentration of Alimemazine can be increased when it is combined with Atovaquone.Approved, Vet Approved
ArtemetherThe risk or severity of adverse effects can be increased when Artemether is combined with Atovaquone.Approved
BL-1020The serum concentration of BL-1020 can be increased when it is combined with Atovaquone.Investigational
ChlorpromazineThe serum concentration of Chlorpromazine can be increased when it is combined with Atovaquone.Approved, Vet Approved
DapsoneThe risk or severity of adverse effects can be increased when Atovaquone is combined with Dapsone.Approved, Investigational
EfavirenzThe serum concentration of Atovaquone can be decreased when it is combined with Efavirenz.Approved, Investigational
EtoposideThe serum concentration of Etoposide can be increased when it is combined with Atovaquone.Approved
FluphenazineThe serum concentration of Fluphenazine can be increased when it is combined with Atovaquone.Approved
IndinavirThe serum concentration of Indinavir can be decreased when it is combined with Atovaquone.Approved
LumefantrineThe risk or severity of adverse effects can be increased when Atovaquone is combined with Lumefantrine.Approved
MesoridazineThe serum concentration of Mesoridazine can be increased when it is combined with Atovaquone.Approved
MethotrimeprazineThe serum concentration of Methotrimeprazine can be increased when it is combined with Atovaquone.Approved
Methylene blueThe serum concentration of Methylene blue can be increased when it is combined with Atovaquone.Investigational
MetoclopramideThe serum concentration of Atovaquone can be decreased when it is combined with Metoclopramide.Approved, Investigational
MoricizineThe serum concentration of Moricizine can be increased when it is combined with Atovaquone.Approved, Withdrawn
PerazineThe serum concentration of Perazine can be increased when it is combined with Atovaquone.Investigational
PerphenazineThe serum concentration of Perphenazine can be increased when it is combined with Atovaquone.Approved
ProchlorperazineThe serum concentration of Prochlorperazine can be increased when it is combined with Atovaquone.Approved, Vet Approved
PromazineThe serum concentration of Promazine can be increased when it is combined with Atovaquone.Approved, Vet Approved
PromethazineThe serum concentration of Promethazine can be increased when it is combined with Atovaquone.Approved
PropiopromazineThe serum concentration of Propiopromazine can be increased when it is combined with Atovaquone.Vet Approved
RifabutinThe serum concentration of Atovaquone can be decreased when it is combined with Rifabutin.Approved
RifampicinThe serum concentration of Atovaquone can be decreased when it is combined with Rifampicin.Approved
RifapentineThe serum concentration of Atovaquone can be decreased when it is combined with Rifapentine.Approved
RitonavirThe serum concentration of Atovaquone can be decreased when it is combined with Ritonavir.Approved, Investigational
TetracyclineThe serum concentration of Atovaquone can be decreased when it is combined with Tetracycline.Approved, Vet Approved
ThiethylperazineThe serum concentration of Thiethylperazine can be increased when it is combined with Atovaquone.Withdrawn
ThioridazineThe serum concentration of Thioridazine can be increased when it is combined with Atovaquone.Approved
TrifluoperazineThe serum concentration of Trifluoperazine can be increased when it is combined with Atovaquone.Approved
TriflupromazineThe serum concentration of Triflupromazine can be increased when it is combined with Atovaquone.Approved, Vet Approved
Food Interactions
  • Fatty foods increase absorption.
  • Take with food, bioavailability is increased 2 to 3 fold.
References
Synthesis Reference

DrugSyn.org

US5053432
General ReferencesNot Available
External Links
ATC CodesP01AX06
AHFS Codes
  • 08:30.92
PDB EntriesNot Available
FDA labelDownload (63 KB)
MSDSNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.5625
Caco-2 permeable+0.6239
P-glycoprotein substrateSubstrate0.536
P-glycoprotein inhibitor INon-inhibitor0.693
P-glycoprotein inhibitor IINon-inhibitor0.7554
Renal organic cation transporterNon-inhibitor0.7999
CYP450 2C9 substrateNon-substrate0.7986
CYP450 2D6 substrateNon-substrate0.9117
CYP450 3A4 substrateNon-substrate0.5294
CYP450 1A2 substrateInhibitor0.9108
CYP450 2C9 inhibitorInhibitor0.8949
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5773
Ames testNon AMES toxic0.577
CarcinogenicityNon-carcinogens0.9067
BiodegradationNot ready biodegradable0.9922
Rat acute toxicity2.8010 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8511
hERG inhibition (predictor II)Non-inhibitor0.8037
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
SuspensionOral750 mg
SuspensionOral750 mg/5mL
TabletOral250 mg
Prices
Unit descriptionCostUnit
Malarone 250-100 mg tablet7.7USD tablet
Mepron 750 mg/5 ml suspension4.95USD ml
Malarone 62.5-25 mg tablet4.33USD tablet
Mepron 150 mg/ml Suspension2.89USD ml
Malarone 62.5-25 mg ped tablet2.72USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2150234 No2005-03-222013-11-25Canada
CA2152615 No2001-10-162013-12-23Canada
US5998449 No1994-05-252014-05-25Us
US6649659 Yes1997-01-102017-01-10Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubilityPractically insolubleNot Available
logP5.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000796 mg/mLALOGPS
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 Area54.37 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity103.11 m3·mol-1ChemAxon
Polarizability39.55 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as naphthoquinones. These are compounds containing a naphthohydroquinone moiety, which consists of a benzene ring linearly fused to a bezene-1,4-dione (quinone).
KingdomOrganic compounds
Super ClassBenzenoids
ClassNaphthalenes
Sub ClassNaphthoquinones
Direct ParentNaphthoquinones
Alternative Parents
Substituents
  • Naphthoquinone
  • Aryl ketone
  • Quinone
  • Halobenzene
  • Chlorobenzene
  • Monocyclic benzene moiety
  • Aryl halide
  • Aryl chloride
  • Vinylogous acid
  • Ketone
  • Enol
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organochloride
  • Organohalogen compound
  • Carbonyl group
  • Aromatic homopolycyclic compound
Molecular FrameworkAromatic homopolycyclic compounds
External DescriptorsNot Available

Targets

Kind
Protein
Organism
Plasmodium falciparum
Pharmacological action
yes
Actions
inhibitor
General Function:
Oxidoreductase activity
Specific Function:
Component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex), which is a respiratory chain that generates an electrochemical potential coupled to ATP synthesis.
Gene Name:
MT-CYB
Uniprot ID:
Q02768
Molecular Weight:
43376.225 Da
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:18082162 ]
  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:10681344 ]
  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:11991686 ]
  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:10447880 ]
  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:10593174 ]
  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:10802314 ]
  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:11181161 ]
  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:12791689 ]
  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:15718226 ]
  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:11906048 ]
Kind
Protein
Organism
Plasmodium falciparum (isolate 3D7)
Pharmacological action
yes
Actions
inhibitor
General Function:
Dihydroorotate dehydrogenase activity
Specific Function:
Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
Gene Name:
Not Available
Uniprot ID:
Q08210
Molecular Weight:
65557.87 Da
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:10681344 ]
  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:7726490 ]
  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:7909690 ]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Ubiquinone binding
Specific Function:
Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
Gene Name:
DHODH
Uniprot ID:
Q02127
Molecular Weight:
42866.93 Da
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:10658902 ]
  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:15044733 ]
  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:7726490 ]
  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:7909690 ]
  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:9425362 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Steroid hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenyto...
Gene Name:
CYP2C9
Uniprot ID:
P11712
Molecular Weight:
55627.365 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Comments
comments powered by Disqus
Drug created on June 13, 2005 07:24 / Updated on December 04, 2016 03:59