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药品详细

Atovaquone(阿托伐醌)

化学结构式图
中文名
阿托伐醌
英文名
Atovaquone
分子式
C22H19ClO3
化学名
2-hydroxy-3-[(1r,4r)-4-(4-chlorophenyl)cyclohexyl]-1,4-dihydronaphthalene-1,4-dione
分子量
Average: 366.837
Monoisotopic: 366.102272181
CAS号
95233-18-4
ATC分类
P01A 未知
药物类型
small molecule
阶段
approved
商品名
同义名
基本介绍

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

生产厂家
    封装厂家
    参考
    Synthesis Reference Not Available
    General Reference Not Available
    剂型
    规格
    化合物类型
    Type small molecule
    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
    适应症
    药理
    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
    理化性质
    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
    药物相互作用
    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
    食物相互作用
    • Fatty foods increase absorption.
    • Take with food, bioavailability is increased 2 to 3 fold.

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