Atovaquone

Antimalarial Agent

The hydroxynaphthoquinone atovaquone, which exhibits antimalarial and anti-Pneumocystis activity, is an electron transport inhibitor that causes depletion of the ATP pool. The primary effect is on the iron flavoprotein dihydro-orotate dehydrogenase, an essential enzyme in the production of pyrimidines. Mammalian cells are able to avoid undue toxicity by use of preformed pyrimidines. Dihydro-orotate dehydrogenase from Plasmodium falciparum is inhibited by concentrations of atovaquone that are very much lower than those needed to inhibit the Pneumocystis enzyme, raising the possibility that the antimicrobial consequences might differ in the two organisms. Although atovaquone was originally developed as a monotherapy for malaria, high level resistance readily emerges in Plasmodium falciparum when the drug is used alone. Consequently, atovaquone is now combined with proguanil.

Description

Atovaquone is an orally active antiprotozoal agent indicated for patients with mild to moderate AIDS-associated Pneumocystis carinii pneumonia who are intolerant to the fist-line therapy of trimethoprim-sulfamethoxazole. It is also under investigation as a treatment for malaria and AIDS-associated toxoplasmosis.

Chemical Properties

Yellow to Orange Crystalline Solid

Originator

Wellcome (United Kingdom)

Uses

Hydroxynaphthoquinone derivative that inhibits mitochondrial electron transport. Antipneumocystic

Uses

beta-adrenergic blocker

Uses

Atovaquone inhibits the cytochrome bc(1) complex via interactions with the Rieske iron-sulfur protein and cytochrome b in the ubiquinol oxidation pocket. In addition to its use as a treatment for toxoplasmosis, atovaquone has antimalarial properties and prevents pneumocystis pneumonia post-renal transplant.

Definition

ChEBI: A naphthoquinone compound having a 4-(4-chlorophenyl)cyclohexyl group at the 2-position and a hydroxy substituent at the 3-position.

Indications

Atovaquone is a naphthoquinone whose mechanism of action involves inhibition of the mitochondrial electron transport system in the protozoa. Malaria parasites depend on de novo pyrimidine biosynthesis through dihydroorotate dehydrogenase coupled to electron transport. Plasmodia are unable to salvage and recycle pyrimidines as do mammalian cells.
Atovaquone is poorly absorbed from the gastrointestinal tract, but absorption is increased with a fatty meal. Excretion of the drug, mostly unchanged, occurs in the feces.The elimination half-life is 2 to 3 days. Low plasma levels persist for several weeks. Concurrent administration of metoclopramide, tetracycline, or rifampin reduces atovaquone plasma levels by 40 to 50%.
Atovaquone has good initial activity against the blood but not the hepatic stage of P. vivax and P. ovale malaria parasites. It is effective against erythrocytic and exoerythrocytic P. falciparum, and therefore, daily suppressive doses need to be taken for only 1 week upon leaving endemic areas.When used alone, it has an unacceptable (30%) rate of recrudescence and selects for resistant organisms. It and proguanil are synergistic when combined and no atovaquone resistance is seen. This combination (Malarone) is significantly more effective than mefloquine, amodiaquine, chloroquine, and combinations of chloroquine, pyrimethamine, and sulfadoxine. In addition to using the combination of atovaquone and proguanil for the treatment and prophylaxis of P. falciparum malaria, atovaquone is also used for the treatment and prevention of P. carinii pneumonia and babesiosis therapy.
Atovaquone is well tolerated and produces only rare instances of nausea, vomiting, diarrhea, abdominal pain, headache, and rash of mild to moderate intensity.

Manufacturing Process

Preparation of intermediate 4-(4-chlorophenyl)cyclohexane-1-carboxylic acid was needed at first. It was made as follows: acetyl chloride (30 g), aluminium chloride (60 g) in carbon disulfide (120 ml) were stirred at -50°C. Cyclohexen (30 g) previously cooled to -50°C was added dropwise during 10 minutes and the mixture was stirred for 60 minutes at -50°C. The solvent was decanted and 300 ml chlorobenzene was added, the so-obtained solution heated at 40°C for 3 hours with stirring, poured onto a mixture of ice and concentrated hydrochloric acid and the organic layer washed with 2 M HCl, 2 M NaOH and water, dried over anhydrous Na2SO4. The product was distilled in vacuo, the fraction boiling at 140°-154°C (0.1 mm Hg) collected, diluted with an equal volume of petroleum ether, cooled to -6°C and a stream of nitrogen gas bubbled through.
3.1 g above obtained hexahydroacetophenone was dissolved in dioxan (15 ml) and the fresh preparated hypobromite (8 ml) in a solution of NaOH (6.2 g) in water (42 ml) at 0°C was added at below 20°C. The mixture was stirred at ambient temperature for 6 hours then allowed to stand overnight. Excess hypobromite was destroyed with sodium metabisulphite, cooled and then acidified to give a colourless solid. It was filtered off, washed with water, dried and recrystallysed from ethanol to give 4-(4-chlorophenyl)cyclohexane-1- carboxylic acid, m.p. 254°-256°C. A mixture of this acid, 2-chloro-1,4- naphthoquinone and silver nitrate was added to ammonium persulfate to give the corresponding naphthoquinone which was saponificated with KOH and was yielded 2-trans-4-(p-chlorophenyl)cyclohexyl)-3-hydroxy-1,4 naphthoquinone, m.p. 216°-219°C, shown by NMR to be the pure trans isomer.

brand name

Mepron (GlaxoSmithKline).

Therapeutic Function

Antiprotozoal

Antimicrobial activity

It is active against erythrocytic, liver and sexual stages of malaria parasites. It shows synergy with proguanil and tetracyclines in vitro. It is also active against Babesia spp. and both tachyzoites and cysts of Tox. gondii. Pn. jirovecii is sensitive in vitro at 0.1–3.0 mg/L and high doses are effective in the rat.

Acquired resistance

Point mutations on parasite cytochrome b, in particular at codon 268, cause resistance and readily occur when the drug is used alone. The rapid selection of resistance led to the development of the synergistic combination with proguanil. Failure of Pn. jirovecii prophylaxis has also been associated with cytochrome b mutations.

General Description

Pharmaceutical secondary standards for application in quality control, provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards.
Atovaquone belongs to the class of naphthoquinones with a broad-spectrum activity against parasitic infections including malaria, toxoplasmosis and Pneumocystis pneumonia. It is a potent antiprotozoal compound which aids in collapsing the mitochondrial membrane potential in a malaria parasite.

Pharmaceutical Applications

A hydroxynaphthoquinone. Available as the trans isomer (which is more active than the cis form) for oral use. It is insoluble in water.

Biochem/physiol Actions

Atovaquone is an anti-protozoal mitochondrial electron transport inhibitor; Antimalarial; Antipneumocystic, and has also been used to treat toxoplasmosis. It is an analog of protozoan mitochondrial protein ubiquinone, and acts by inhibiting the cytochrome bc(1) complex via interactions with the Rieske iron-sulfur protein and cytochrome b in the ubiquinol oxidation pocket.

Mechanism of action

Atovaquone is thought to produce its antiparasitic action by virtue of its ability to inhibit the mitochondrial respiratory chain. More specifically, atovaquone is a ubiquinone reductase inhibitor, inhibiting at the cytochrome bc1 complex. This action leads to a collapse of the mitochondrial membrane potential. The compound shows stereospecific inhibition, with the trans isomer being more active than the cisisomer.

Pharmacokinetics

Oral absorption: Poor
C_max 750 mg oral: 27 mg/L (steady state)
Plasma half-life: 70 h
Plasma protein binding: >99%
It is highly lipophilic and is poorly absorbed from the gastrointestinal tract following oral administration. Bioavailability is improved when administered with meals, particularly those with a high fat content. Steady-state plasma concentrations are up to 50% lower in AIDS patients than in asymptomatic HIV-positive cases and the elimination half-life is lower (55 h) in patients with AIDS. The concentration in CSF is <1% of the plasma level. Unlike some other naphthoquinones it is not metabolized by human liver microsomes. Combinations with co-trimoxazole (in HIV patients) and with proguanil plus artesunate in healthy adults did not produce any changes in atovaquone pharmacokinetics.

Clinical Use

3-[4-(4-Chlorophenyl)-cyclohexyl]-2-hydroxy-1,4-naphthoquinone(Mepron) is a highly lipophilic, water-insolubleanalog of ubiquinone 6, an essential component of the mitochondrialelectron transport chain in microorganisms. Thestructural similarity between atovaquone and ubiquinonesuggests that the former may act as an antimetabolite for thelatter and thereby interfere with the function of electrontransport enzymes.
Atovaquone was originally developed as an antimalarialdrug, but Plasmodium falciparum was found to developa rapid tolerance to its action. More recently, the effectivenessof atovaquone against P. carinii was discovered. Itis a currently recommended alternative to trimethoprimsulfamethoxazole(TMP-SMX) for the treatment and prophylaxisof PCP in patients intolerant to this combination.Atovaquone was also shown to be effective in eradicatingT. gondii in preclinical animal studies.
The oral absorption of atovaquone is slow and incomplete,in part because of the low water solubility of the drug.Aqueous suspensions provide significantly better absorptionthan do tablets. Food, especially if it has a high fat content,increases atovaquone absorption. Significant enterohepaticrecycling of atovaquone occurs, and most (nearly 95%) ofthe drug is excreted unchanged in the feces. In vivo, atovaquoneis largely confined to the plasma, where it is extensivelyprotein bound ( 99.9%). The half-life of the drugranges from 62 to 80 hours. The primary side effect is gastrointestinalintolerance.

Clinical Use

Pn. jirovecii pneumonia; alternative therapy for mild to moderate illness (prophylaxis and treatment)
Prophylaxis and treatment of malaria in combination with proguanil
It has also been used in cerebral toxoplasmosis in AIDS patients and in a few cases of human babesiosis.

Side effects

Most clinical trials of atovaquone alone have involved patients with AIDS in whom adverse effects are often difficult to detect; however, more than 20% reported fever, nausea, diarrhea and rashes. There were limited changes in hepatocellular function. In malaria, in combination with proguanil, there are few reported side effects.

Veterinary Drugs and Treatments

Atovaquone (with azithromycin) appears effective in treating dogs with Babesia gibsoni (Asian genotype) infections, particularly in dogs not immunosuppressed or splenectomized. Atovaquone may be of benefit for treating pneumocystosis in dogs, but it is considered second line therapy after potentiated sulfonamides. Atovaquone (with azithromycin) may be of benefit in treating Cytauxzoon felis infections in cats (research is in progress at the time of writing).

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: avoid with rifabutin, concentration of both drugs reduced; avoid with rifampicin, concentration reduced and rifampicin concentration increased; concentration reduced by tetracycline.
Antivirals: concentration reduced by efavirenz - avoid; concentration of indinavir possibly reduced; concentration of zidovudine increased.
Metoclopramide: significant reduction in plasma atovaquone levels.

Metabolism

Atovaquone is poorly absorbed from the GI tract because of its poor water solubility and high fat solubility, but the absorption can be significantly increased if taken with a fat-rich meal. The drug is highly bound to plasma protein (94%) and does not enter the CNS in significant quantities. It is not significantly metabolized in humans and is exclusively eliminated in feces via the bile.