Synergy of mefloquine activity with atorvastatin, but not chloroquine and monodesethylamodiaquine, and association with the pfmdr1 gene.
OBJECTIVE
The aim of the study was to assess the in vitro potentiating effects of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, in combination with mefloquine, chloroquine or monodesethylamodiaquine against Plasmodium falciparum and to evaluate whether the effects of atorvastatin could be associated with mutations or gene copy number in multidrug resistance (MDR)-like protein genes.


METHODS
The susceptibilities of 21 parasite strains to combinations of atorvastatin with mefloquine, chloroquine or monodesethylamodiaquine were assessed using the in vitro isotopic microtest. Genotypes and gene copy number were assessed for pfmdr1, pfmdr2 and pfmrp genes.


RESULTS
Atorvastatin demonstrated synergistic effects in combination with mefloquine. The mefloquine IC(50) (50% inhibitory concentration) was reduced by 7%, 24% and 37% in the presence of atorvastatin at concentrations of 0.1, 0.5 and 1.0 microM, respectively. The synergistic effect of atorvastatin on the response to mefloquine was significantly associated with pfmdr1 copy number. The concentration of atorvastatin that could reduce the IC(50) of mefloquine by 50% was 2.4 +/- 1.3 microM for the 12 strains that contained one copy of pfmdr1 and 5.8 +/- 2.1 microM for the 9 strains that contained two copies or more. The synergistic effect of atorvastatin in combination with mefloquine was found to be significantly unrelated to mutations in pfmdr1, pfmdr2 or pfmrp genes.


CONCLUSIONS
The synergy of the effect of mefloquine at concentrations relevant to its achievable plasma concentrations in patients taking 80 mg of atorvastatin daily suggests that atorvastatin will be a good candidate in combination with mefloquine for malaria treatment.
Wurtz
Nathalie
N
Unité de Recherche en Physiologie et Pharmacocinétique Parasitaires - UMR-MD3 Relations Hôte-Parasites - Pharmacologie et Thérapeutique, Institut de Recherche Biomédicale des Armées, antenne de Marseille, Marseille, France.
Briolant
Sébastien
S
Gil
Marine
M
Parquet
Véronique
V
Henry
Maud
M
Baret
Eric
E
Amalvict
Rémy
R
Almeras
Lionel
L
Rogier
Christophe
C
Pradines
Bruno
B
D000655:Amodiaquine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000962:Antimalarials / Q000494:pharmacology*; D000069059:Atorvastatin; D002738:Chloroquine / Q000494:pharmacology*; D016054:DNA, Protozoan / Q000235:genetics; D004357:Drug Synergism; D018628:Gene Dosage; D005838:Genotype; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D015767:Mefloquine / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D011758:Pyrroles / Q000494:pharmacology*
D000655:Amodiaquine; D000962:Antimalarials; D000069059:Atorvastatin; D002738:Chloroquine; D016054:DNA, Protozoan; D006538:Heptanoic Acids; D015767:Mefloquine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011758:Pyrroles; C513498:Mdr1 protein, Plasmodium falciparum; C513499:Mdr2 protein, Plasmodium falciparum; C047386:desethylamodiaquine