The online version of this article (doi:10.1186/1475-2875-11-177) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
KC: designed and conducted the experiments, performed the data analysis and wrote manuscript. MM: technical support and data collection. RR and SP: patient recruitment and patient care, blood collection. RU: laboratory support and revised manuscript. AMD: data analysis and revised manuscript. PS: volunteer recruitment and blood collection. NJW: study design, data analysis and contributed to writing the manuscript. All authors have seen and approved this manuscript.
Lumefantrine and atovaquone are highly lipophilic anti-malarial drugs. As a consequence absorption is increased when the drugs are taken together with a fatty meal, but the free fraction of active drug decreases in the presence of triglyceride-rich plasma lipoproteins. In this study, the consequences of lipidaemia on anti-malarial drug efficacy were assessed in vitro.
Serum was obtained from non-immune volunteers under fasting conditions and after ingestion of a high fat meal and used in standard Plasmodium falciparum in-vitro susceptibility assays. Anti-malarial drugs, including lumefantrine, atovaquone and chloroquine in five-fold dilutions (range 0.05 ng/ml – 1 ug/mL) were diluted in culture medium supplemented with fasting or post-prandial 10% donor serum. The in-vitro drug susceptibility of parasite isolates was determined using the 3H-hypoxanthine uptake inhibition method and expressed as the concentration which gave 50% inhibition of hypoxanthine uptake (IC50).
Doubling plasma triglyceride concentrations (from 160 mg/dL to 320 mg/dL), resulted in an approximate doubling of the IC50 for lumefantrine (191 ng/mL to 465 ng/mL, P < 0.01) and a 20-fold increase in the IC50 for atovaquone (0.5 ng/mL to 12 ng/ml; P < 0.01). In contrast, susceptibility to the hydrophilic anti-malarial chloroquine did not change in relation to triglyceride content of the medium.
Lipidaemia reduces the anti-malarial activity of lipophilic anti-malarial drugs. This is an important confounder in laboratory in vitro testing and it could have therapeutic relevance.
Authors’ original file for figure 112936_2011_2154_MOESM1_ESM.pdf
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- The effects of serum lipids on the in vitro activity of lumefantrine and atovaquone against Plasmodium falciparum
Arjen M Dondorp
Nicholas J White
- BioMed Central
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