Banner
targets (3) enzymes (1)
for drugs
Identification
Name Atovaquone
Accession Number DB01117 (APRD00805)
Type small molecule
Groups approved
Description

A hydroxynaphthoquinone that has antimicrobial activity and is being used in antimalarial protocols. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Salts Not Available
Brand names
Name Company
Malarone Pediatric
Brand mixtures
Brand Name Ingredients
Malarone Atovaquone + Proguanil Hydrochloride
Malarone Pediatric Atovaquone + Proguanil Hydrochloride
Categories
  • Anti-Infective Agents
  • Enzyme Inhibitors
  • Antimalarials
  • Antifungal Agents
  • Antiprotozoal Agents
CAS number 95233-18-4
Weight Average: 366.837
Monoisotopic: 366.102272181
Chemical Formula C22H19ClO3
InChI Key InChIKey=KUCQYCKVKVOKAY-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-
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Naphthoquinones
Substructures
  • Hydroxy Compounds
  • Benzyl Alcohols and Derivatives
  • Naphthalenes
  • Phenylpropenes
  • Benzoquinones
  • Benzene and Derivatives
  • Naphthoquinones
  • Aryl Halides
  • Halobenzenes
  • Aromatic compounds
  • Cinnamaldehydes
  • Benzoyl Derivatives
  • Enols
  • Ketones
Pharmacology
Indication For 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.
Pharmacodynamics Atovaquone 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 action Atovaquone 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.
Absorption The 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 binding Atovaquone 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 elimination The 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 life 2.2 to 3.2 days
Clearance
  • 10.4 +/- 5.5 ml/min [HIV-infected patients receiving IV administration]
Toxicity The 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
Pathways Not Available
Pharmacoeconomics
Manufacturers Not Available
Packagers
Dosage forms
Form Route Strength
Suspension Oral
Prices
Unit description Cost Unit
Malarone 250-100 mg tablet 7.7 USD tablet
Mepron 750 mg/5 ml suspension 4.95 USD ml
Malarone 62.5-25 mg tablet 4.33 USD tablet
Mepron 150 mg/ml Suspension 2.89 USD ml
Malarone 62.5-25 mg ped tablet 2.72 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 5998449 1994-05-25 2014-05-25
Canada 2150234 2005-03-22 2013-11-25
Canada 2152615 2001-10-16 2013-12-23
Properties
State solid
Experimental Properties
Property Value Source
water solubility Practically insoluble Not Available
logP 5.8 Not Available
Predicted Properties
Property Value Source
water solubility 7.96e-04 g/l ALOGPS
logP 4.74 ALOGPS
logP 5 ChemAxon
logS -5.7 ALOGPS
pKa (strongest acidic) 8.23 ChemAxon
pKa (strongest basic) -4.1 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 3 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 54.37 ChemAxon
rotatable bond count 2 ChemAxon
refractivity 103.11 ChemAxon
polarizability 39.55 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00236 Link_out
PubChem Compound 74989 Link_out
PubChem Substance 46507298 Link_out
ChemSpider 67544 Link_out
BindingDB 16301 Link_out
ChEBI 575568 Link_out
ChEMBL 575568 Link_out
Therapeutic Targets Database DAP000156 Link_out
PharmGKB PA448502 Link_out
Drug Product Database 2217422 Link_out
RxList http://www.rxlist.com/cgi/generic/atovaqu.htm Link_out
Drugs.com http://www.drugs.com/cdi/atovaquone.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Atovaquone Link_out
ATC Codes
  • P01AX06
AHFS Codes
  • 08:30.92
PDB Entries Not Available
FDA label show (63 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Rifabutin Rifabutin decreases the effect of atovaquone
Rifampin Rifampin may decrease the effect of atovaquone.
Tetracycline Tetracycline may decrease the effect of atovaquone.
Zidovudine Atovaquone 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

Pharmacological action: yes
Actions: inhibitor

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 (By similarity)

Organism class: parasitic
UniProt ID: Q02768 Link_out
Gene: MT-CYB Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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 homolog, mitochondrial

Pharmacological action: yes
Actions: inhibitor
Organism class: parasitic
UniProt ID: Q08210 Link_out
Gene: PFF0160c
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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, mitochondrial

Pharmacological action: unknown
Actions: inhibitor
Organism class: human
UniProt ID: Q02127 Link_out
Gene: DHODH Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inhibitor

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, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19