Influence of lipid lowering fibrates on P-glycoprotein activity in vitro

Ehrhardt, Manuela; Lindenmaier, Heike; Burhenne, Jürgen; Haefeli, Walter E.; Weiß, Johanna

doi:10.1016/j.bcp.2003.09.008

Cited by 39 publications

(20 citation statements)

References 30 publications

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“…The mean ± SD indicate standard deviation, a value of p ≤ 0.05 (*) or a value of p ≤ 0.01 (**) was considered as signifi cant. Ciglitazone Rosiglitazone Troglitazone previous one, but transfected with gene coding MDR1) [24]. These studies confirm negative regulation of MDR1 by PPAR-γ.…”

Section: Discussionsupporting

confidence: 73%

Thiazolidinediones Regulate the Level of ABC Transporters Expression on Lung Cancer Cells

Konieczna¹,

Nováková²,

Medalová³

et al. 2015

Klin Onkol

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SummaryATP binding cassette (ABC) transporters related to multidrug resistance (MDR) actively effl ux various xenobio tics from the cells across the cell membrane and decrease a drug's effi ciency. Lung cancer is the leading cause of death among all types of cancer in the Czech Republic, and its incidence is still rising. Ciglitazone, rosiglitazone and troglitazone belonging to PPAR-γ agonist family (formerly used in diabetes mellitus treatment) were selected to investigate their capability to infl uence expression of ABC transporters on lung cancer cells. Therefore, the eff ect of PPAR-γ of agonists on transcription of following ABC transporters was investigated: multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP). We have investigated if these PPAR-γ agonists are substrates of ABC transporters using HL60 and HL60 derived cell lines (HL60-MDR1, HL60-MRP1, PLB-BCRP) by cytotoxicity test WST-1. We have mapped the changes in mRNA expression level of those transporters in A549 and HEK293 cells after PPAR-γ agonists treatment using quantitative reverse transcription real-time PCR (qRT-PCR). All three PPAR-γ agonists serve as substrates to at least one ABC transporter under study. PPAR-γ activation correlates with up-regulation of PTEN which may modulate the expression of ABC transporters through PI3K/ Akt signaling pathway. We have shown that rosiglitazone and troglitazone inhibit mRNA expression of MDR1 transporter in both cell lines whereas the expression of MRP1 in HEK293 cell was up-regulated after rosiglitazone treatment and the expression of MDR1 was upregulated after ciglitazone treatment.

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Section: Discussionsupporting

confidence: 73%

Thiazolidinediones Regulate the Level of ABC Transporters Expression on Lung Cancer Cells

Konieczna¹,

Nováková²,

Medalová³

et al. 2015

Klin Onkol

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“…Twenty-seven compounds were investigated in all three cell systems, 35 in two systems, and 16 in only one cell system. Among them were highly potent P-gp inhibitors like LY335979 (zosuquidar), SDZ-PSC833 (valspodar), and GG918 (elacridar), drugs used for HIV therapy, fungicides, newer antidepressants (Weiss et al, 2003a), progestins (Frö hlich et al, 2004), fibrates (Ehrhardt et al, 2004), amphetamines (KetabiKiyanvash et al, 2003), antiepileptic drugs (Weiss et al, 2003b), and kava-kava extracts and kavalactones (Weiss et al, 2005). Of all these compounds, 21 revealed no P-gp inhibition up to the highest soluble concentration (10 in P388/dx cells, 19 in L-MDR1 cells, and 11 in pBCECs).…”

Section: Resultsmentioning

confidence: 99%

EVALUATION OF INHIBITORY POTENCIES FOR COMPOUNDS INHIBITING P-GLYCOPROTEIN BUT WITHOUT MAXIMUM EFFECTS: F₂ VALUES

Weiß

Haefeli²

2005

Drug Metab Dispos

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ABSTRACT:In cell culture systems with aqueous buffers, concentration-response curves to lipophilic inhibitors are difficult to establish because plateau effects (I max ) are often not reached because of limited drug solubility. Consequently, the inhibitory potency of a compound will not be definable using IC 50 values (concentration exerting 50% of I max ). Since alternative potency measures f 2 values, the concentrations required to double baseline signals have been proposed. Using both methods, we reevaluated the concentration-response curves of calcein assays with 78 compounds in three different cell culture systems and found a close correlation between both methods (r s ‫؍‬ 0.93-0.99, p < 0.0028). These findings suggest that f 2 values are a valuable alternative to define rank orders of highly lipophilic inhibitors as a basis for the prediction of pharmacological interaction properties in clinical settings. Although it was only tested for inhibition of P-glycoprotein, it seems likely that this method may be transferred to other assays with other proteins.The assessment of the concentration-response relationship is a key element in the pharmacologic characterization of inhibitors of important targets like the ATP-binding cassette (ABC) transporter Pglycoprotein (P-gp; MDR1/ABCB1). The inhibitory potency of a compound is normally expressed as IC 50 (concentration leading to half-maximal inhibition) and is typically derived from the Hill equation or its derivatives,which describe concentration-response curves using four parameters: background (I min ), maximum effect (I max ), slope (s), and IC 50 , the concentration leading to 50% of I max . Obviously, the accurate determination of IC 50 values depends on the reliable description of I min , s, and I max , with the latter being the most challenging, since maximum effects can often not be reached because of limited solubility or cytotoxic effects. We have previously shown that the poor solubility is frequently neglected and that numerous papers report having tested inhibition at drug concentrations beyond the maximum solubility of the inhibitor in the respective buffers (Weiss et al., 2002).In this study we have evaluated an alternative method to assess the inhibitory potency of compounds interacting with P-gp, the substrates of which are typically highly lipophilic and typically cannot be tested up to maximal effects in vitro because of their low solubility in the aqueous solutions used in cell culture systems. P-gp inhibition was investigated with the well established and widely used calcein assay in three different cell systems expressing moderate to high amounts of this efflux transporter: primary porcine brain capillary endothelial cells (pBCECs), L-MDR1 cells with overexpression of human P-gp, and the murine leukemic cell line P388/dx overexpressing murine P-gp. Materials and MethodsMaterials. Culture media, fetal calf serum, medium supplements, antibiotics, and Hanks' balanced salt solution were purchased from Invitrogen (Karlsruhe, Germany), dimethyl sul...

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“…If fibrates act through inhibition of Pgh1, as might be predicted (19), a synergistic interaction with reversal of CQ resistance would have occurred. Fenofibric acid and clofibrate appeared to be less active against W2mef than 3D7, suggesting that they, like CQ, are exerting their effect within the food vacuole and are at risk of drug efflux mechanisms in CQ-resistant parasites.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequent studies have provided indirect evidence that fibrates might have therapeutic potential in malaria. One study showed that fenofibrate was the only member of the fibrate class to inhibit P-glycoprotein-mediated transport (19). This finding suggests that fenofibrate might also inhibit the P-glycoprotein homologue 1 (Pgh1) in P. falciparum and, thus, through reduced efflux of chloroquine (CQ) and mefloquine, reverse resistance (32).…”

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confidence: 99%

In Vitro Antimalarial Activity and Drug Interactions of Fenofibric Acid

Wong¹,

Davis²

2012

Antimicrob Agents Chemother

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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 ...

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Influence of lipid lowering fibrates on P-glycoprotein activity in vitro

Cited by 39 publications

References 30 publications

Thiazolidinediones Regulate the Level of ABC Transporters Expression on Lung Cancer Cells

Thiazolidinediones Regulate the Level of ABC Transporters Expression on Lung Cancer Cells

EVALUATION OF INHIBITORY POTENCIES FOR COMPOUNDS INHIBITING P-GLYCOPROTEIN BUT WITHOUT MAXIMUM EFFECTS: F₂ VALUES

In Vitro Antimalarial Activity and Drug Interactions of Fenofibric Acid

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Influence of lipid lowering fibrates on P-glycoprotein activity in vitro

Cited by 39 publications

References 30 publications

Thiazolidinediones Regulate the Level of ABC Transporters Expression on Lung Cancer Cells

Thiazolidinediones Regulate the Level of ABC Transporters Expression on Lung Cancer Cells

EVALUATION OF INHIBITORY POTENCIES FOR COMPOUNDS INHIBITING P-GLYCOPROTEIN BUT WITHOUT MAXIMUM EFFECTS: F2 VALUES

In Vitro Antimalarial Activity and Drug Interactions of Fenofibric Acid

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EVALUATION OF INHIBITORY POTENCIES FOR COMPOUNDS INHIBITING P-GLYCOPROTEIN BUT WITHOUT MAXIMUM EFFECTS: F₂ VALUES