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Safety of antimalarial drug atovaquone from the aspect of genotoxicity: an alkaline comet assay study on human lymphocytes

Since malariaremains one of the major global health problem there are various drugs widely used in prophylaxis and treatment of this disease, one of them being atovaquone whichusuallycomes in fixed combination with proguanil. For the prevention of malaria in travelers, antimalarial agents should fulfill the requirements of efficacy towards the parasite, in addition to being safe towards the consumer and not putting them at additional risk of adverse effects.Present study aimed to investigate the genotoxic potential of clinically relevant concentrations of atovaquone in human lymphocytes in vitro.Although a specific metabolite of atovaquone has not been identified, testing was done with and without metabolic activation (S9). Concentrations usedin the present study were obtained from the plasma concentrations after administration of a fixed-dose combination with proguanil: 2950 ng/ml used for prophylactic treatment and 11800 ng/ml used in treatment of malaria. Genotoxic potential was measured with the alkalinecomet assay. None of the determined comet assay parameters (tail length, tail intensity and tail moment) showed significant increaseafter the treatment comparedwith the corresponding control samples. When comparing mean values between different concentrations and exposure times, there were no changes as well. Addition of metabolic activation also did not induce any significant changes in either comet assay parameter. Obtained results indicate that atovaquone did not cause any DNA damaging effect in human lymphocytes after treatment in both concentrations, independent of exposure time or addition of metabolic activation. Thus it is to be presumed that atovaquone in tested concentrations is not genotoxic. Since addition of metabolic activation did not cause any significant changes compare to treatment without metabolic activation it is to be presumed that atovaquone has no metabolite or it is not toxic as well. In conclusion, our results indicate that atovaquone is highly safe for consumption from the aspect of genotoxicity, when used as prophylactic treatment or in the treatment of malaria.

atovaquone ; DNA damage ; comet assay ; human lymphocytes ; metabolic activation

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