Drug Groups

approved

Description

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

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.

Pharmacology

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.

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

Biotransformation

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

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%.

Half Life

2.2 to 3.2 days

Protein Binding

Atovaquone is extensively bound to plasma proteins (99.9%) over the concentration range of 1 to 90 µg/mL.

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%).

Distribution

* 0.60 ± 0.17 L/kg

Clearance

* 10.4 +/- 5.5 ml/min [HIV-infected patients receiving IV administration]

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