The effects of serum lipids on the in vitro activity of lumefantrine and atovaquone against Plasmodium falciparum.
BACKGROUND
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.


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
MORU, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Rd, Bangkok 10400, Thailand.
Kesinee
K
Chotivanich
Mathirut
M
Mungthin
Ronnatrai
R
Ruengweerayuth
Rachanee
R
Udomsangpetch
Arjen M
AM
Dondorp
Pratap
P
Singhasivanon
Sasithon
S
Pukrittayakamee
Nicholas J
NJ
White
D000962:Antimalarials / Q000494:pharmacology*; D053626:Atovaquone / Q000494:pharmacology*; D004983:Ethanolamines / Q000494:pharmacology*; D005449:Fluorenes / Q000494:pharmacology*; D006805:Human Experimentation; D006801:Humans; D020128:Inhibitory Concentration 50; D008055:Lipids / Q000032:analysis*; D000078102:Lumefantrine; D021261:Parasitic Sensitivity Tests / Q000379:methods; D010963:Plasmodium falciparum / Q000187:drug effects*; D044967:Serum / Q000737:chemistry*
D000962:Antimalarials; D004983:Ethanolamines; D005449:Fluorenes; D008055:Lipids; D000078102:Lumefantrine; D053626:Atovaquone