In Vitro Antimalarial Activity and Drug Interactions of Fenofibric Acid

Abstract

Plasmodium falciparum has developed resistance to most available treatments, underscoring the need for novel antimalarial drugs. Fibrates are lipid-modifying agents used to reduce morbidity and mortality associated with cardiovascular disease. They may have antimalarial activity through modulation of P-glycoprotein and ATP-binding cassette subfamily A member (ABC-1)-mediated nutrient transport and/or via a putative peroxisome proliferator-activated receptor alpha-like protein. We therefore examined in vitro antimalarial activities of fibrates and their interactions with chloroquine and dihydroartemisinin in chloroquine-sensitive (3D7) and chloroquine-resistant (W2mef) strains of P. falciparum using the conventional isotopic assay microtechnique. A bioassay was used to assess inhibition activities of human plasma after therapeutic fenofibrate doses. Fenofibric acid, the main metabolite of fenofibrate, was the most potent of the fibrates tested, with mean 50% inhibitory concentrations of 152 nM and 1,120 nM for chloroquine-sensitive and -resistant strains, respectively. No synergistic interaction between fibrates and chloroquine or dihydroartemisinin was observed. Plasma fenofibric acid concentrations, quantified by high-performance liquid chromatography in seven healthy volunteers after treatment (mean, 15.3 mg/liter, or 48 M), inhibited P. falciparum. BLAST analysis revealed the likely presence of an ABC-1 transporter homolog in P. falciparum. Our findings demonstrate that fenofibric acid has activity similar to the activities of conventional antimalarial drugs at concentrations well below those achieved after therapeutic doses. It may inhibit P. falciparum growth by inhibiting intracellular lipid transport.T he progressive increase in drug-resistant malaria, including the recent emergence of delayed clearance of Plasmodium falciparum after treatment with artemisinin derivatives (8,16,36), highlights the need for novel effective antimalarial drugs. One possible source is compounds which have been approved for other indications but which are found to have parasiticidal or diseasemodifying effects in malaria infection. Given prior detailed knowledge of their pharmacokinetic properties, safety, and tolerability, it is likely that such compounds can be fast-tracked through the usual drug development process. Examples that may prove to be pertinent to the treatment of human malaria are the glitazone drug rosiglitazone (4) and the 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor atorvastatin (30,31,34).Fibrates such as gemfibrozil and fenofibrate are agonists of peroxisome proliferator-activated receptor alpha (PPAR␣) that are in relatively widespread clinical use as potent lipid-modifying drugs (13). The first study of fibrates in malaria found that clofibrate directly inhibited the development of parasitemia in P. berghei-infected mice (27). Subsequent studies have provided indirect evidence that fibrates might have therapeutic potential in malaria. One study showed that fenofibrate was the only member of ...

Investigation of the Plasmodium falciparum Food Vacuole through Inducible Expression of the Chloroquine Resistance Transporter (PfCRT)

“…From a total of five independent experiments, each with three internal replicates, the IC 50 value for 3D7 wild-type parasites using this experimental method was on average 18.9±3.8 nM, and W2mef parasites had an IC 50 for chloroquine of 295.3±21.0. ( Table 1 ) These IC 50 values are consistent with 48 hour IC 50 s previously reported for these strains [59] , [60] . Parasites transfected with the PfCRT-GFP plasmids but with transgene expression repressed by maintenance on ATc showed no significant difference in the IC 50 compared to 3D7 (t-test p>0.05).…”

Determination of Fenofibric Acid in Human Plasma by LC–MS/MS and LC–UV

“…1a), is used for hypercholesterolemia and hypertriglyceridemia to reduce morbidity and mortality associated with cardiovascular disease as a lipid regulating agent [1][2][3][4]. FF is absorbed from the gastrointestinal tract, and is principally hydrolysed by the CYP3A4 isozyme to its active and major metabolite fenofibric acid (FFA, Fig.…”

A Novel Method for Determination of Fenofibric Acid in Human Plasma using HPLC-UV: Application to a Pharmacokinetic Study of New Formulations

“…Chemically, FBT is 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester. Fenofibric acid (Figure 1b), the active metabolite of FBT, contributes to a reduction in total cholesterol, LDL cholesterol, apolipoprotien B, total triglycerides and triglyceride rich lipoprotein [2][3][4][5][6][7]. In addition, treatment with FBT also results in elevation of high-density lipoprotein (HDL) and apoproteins, viz., apoAI and apoAII.…”