Interactions of racemic mefloquine and its enantiomers with P-glycoprotein in an immortalised rat brain capillary endothelial cell line, GPNT

Pham, Yen-Thu; Régina, Anthony; Farinotti, Robert; Couraud, Pierre‐Olivier; Wainer, Irving W.; Roux, F.; Gimenez, François

doi:10.1016/s0304-4165(00)00160-4

Cited by 69 publications

(52 citation statements)

References 23 publications

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“…While chloroquine, mefloquine, quinine, and pyronaridine are weak P-gp substrates, they inhibit the efflux of other P-gp substrates (8,9,11,14). Although our experiments did not assess whether the present antimalarial drugs behave in the same way, our results suggest limited P-gp-mediated pyronaridine and naphthoquine efflux at low micromolar concentrations.…”

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confidence: 58%

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Role of P Glycoprotein in Absorption of Novel Antimalarial Drugs

Crowe

Ilett

Karunajeewa

et al. 2006

Antimicrob Agents Chemother

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Bidirectional transport of four novel antimalarial compounds was determined using Caco-2 cell monolayers. P glycoprotein-mediated efflux was greatest for pyronaridine (5 to 20 M) and low for naphthoquine (5 M). With 20 M naphthoquine, net efflux was blocked, suggesting saturation of the transporter. Piperaquine and dihydroartemisinin were not transported by the system. Permeability glycoprotein (P-gp) ATP-dependent transporters influence the passage of many drugs across epithelial barriers in the intestine, brain, liver, and kidney (1) and may alter their pharmacokinetic and/or pharmacodynamic properties. Several antimalarial drugs are substrates and/or inhibitors of P-gp (9, 10, 15). In the intestine, P-gp has a secretory function which can contribute to low bioavailability and substrate-inhibitor interactions (14). The antimalarials dihydroartemisinin, naphthoquine, piperaquine, and pyronaridine are highly lipid soluble, with logP (log octanol-water partition coefficient) values of 2.6, 6.16, 6.16, and 4.98, respectively (ACD I Lab Software version 8.14 for Solaris; ACD Labs, Toronto, Canada). Evidence suggests that dihydroartemisinin and piperaquine have oral bioavailabilities of Ͻ50% (6, 7), while pyronaridine may interfere with P-gp-mediated transport (10, 11). We therefore investigated whether these four drugs are P-gp substrates and whether P-gp-mediated efflux explains the apparently low bioavailabilities of dihydroartemisinin and piperaquine.Drug transport was studied with an in vitro gastrointestinal model by using a monolayer of a CLEFF9 subclone of human Caco-2 cells with high P-gp-mediated efflux (4) and previously reported experimental protocols (3-5). Briefly, cells were seeded onto 0.6-cm 2 polycarbonate filters in 24-well plates and grown in high-glucose Dulbecco's modified Eagle's medium for 3 weeks. Following incubation in buffered Hanks balanced salt solution (HBSS) with or without specific efflux inhibitors for 30 min at 37°C, transepithelial electrical resistance was measured and assay medium/inhibitors were placed in the receiver chambers. Antimalarial drugs were added to the donor chamber of each well. The apical and basolateral chambers received 0.3 and 0.6 ml medium, respectively. Transepithelial electrical resistance measurements were repeated at the conclusion of the studies to ensure continued monolayer integrity.Naphthoquine was assayed using high-performance liquid chromatography (HPLC) with UV detection at 260 nm after separation through an Eclipse XDB-C 8 column (Agilent Technologies, Forest Hill, Australia) with a mobile phase of 22% acetonitrile, 10% methanol, and 68% 20 mM KH 2 PO 4 , with 11 mM triethylamine and 0.1% trifluoroacetic acid pumped at 1.2 ml/min. The limit of detection (LOD) was 30 nM. Pyronaridine was assayed by HPLC with detection at 277 nm after separation through a 100-by 4.6-mm (inside diameter), 3.5-m XTerra C 18 column (Waters Associates, Milford, MA), with acetonitrile buffer (80 mM KH 2 PO 4 , 22 mM triethylamine HCl, and 0.1% trifluoroacetic acid, pH 2....

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mentioning

confidence: 58%

“…Several antimalarial drugs are substrates and/or inhibitors of P-gp (9,10,15). In the intestine, P-gp has a secretory function which can contribute to low bioavailability and substrate-inhibitor interactions (14).…”

mentioning

confidence: 99%

Role of P Glycoprotein in Absorption of Novel Antimalarial Drugs

Crowe

Ilett

Karunajeewa

et al. 2006

Antimicrob Agents Chemother

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“…In in vitro studies, mefloquine has been shown to interact with a number of potential neurological targets, including neuronal calcium homeostasis, the endoplasmic reticulum calcium pump, acetylcholinesterase, blood-brain barrier P glycoproteins, glutaminergic synaptic activity, connexins, A 2 a receptors, and potassium and anion channels (6,8,16,17,21,22,24,30,44). The A 2 a receptor is a strong candidate for potential involvement, given its suspected role in sleep modulation and its potent inhibition by mefloquine (41,42,44).…”

Section: Discussionmentioning

confidence: 99%

“…This is probably due to a combination of factors, including (i) lack of formal diagnostic criteria (case definition), (ii) varying definitions of neurological effects, (iii) varying definitions of mild versus severe effects, and (iv) differences in protocols used for data collection (11,35). Finally, in vitro studies have shown that mefloquine interacts with a bewildering array of protein targets and cellular signaling pathways (6,8,16,17,21,22,24,30,44), any of which may or may not be clinically important. As a first step in the direction of rendering these challenges more tractable, a proof-ofconcept in vivo neurological evaluation of the effects of meflo-quine would be invaluable.…”

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confidence: 99%

Mefloquine Induces Dose-Related Neurological Effects in a Rat Model

Dow¹,

Bauman²,

Caridha³

et al. 2006

Antimicrob Agents Chemother

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Mefloquine is one of the drugs approved by the FDA for malaria chemoprophylaxis. Mefloquine is also approved for the treatment of malaria and is widely used for this purpose in combination with artesunate. However, the clinical utility of the compound has been compromised by reports of adverse neurological effects in some patients. In the present study, the potential neurological effects of mefloquine were investigated with six 7-week-old female rats given a single oral dose of the compound. Potential mefloquine-induced neurological effects were monitored using a standard functional observational battery, automated open field tests, automated spontaneous activity monitoring, a beam traverse task, and histopathology. Plasma mefloquine concentrations were determined 72 h after dosing by using liquid chromatography-mass spectrometry. Mefloquine induced dose-related changes in endpoints associated with spontaneous activity and impairment of motor function and caused degeneration of specific brain stem nuclei (nucleus gracilis). Increased spontaneous motor activity was observed only during the rats' normal sleeping phase, suggesting a correlate to mefloquine-induced sleep disorders. The threshold dose for many of these effects was 187 mg/kg of body weight. This dose yielded plasma mefloquine concentrations after 72 h that are similar to those observed in humans after the treatment dose. Collectively, these data suggest that there may be a biological basis for some of the clinical neurological effects associated with mefloquine.

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“…In an immortalized rat brain capillary endothelial cell line, GPNT cells, (+)-MQ produced an eight-fold greater inhibition of VBL transport than (−)-MQ (Pham et al 2000). However, the MQ inhibition of VBL transport was not enantioselective in Caco-2 cells.…”

Section: Determination Of Stereoselective Ligand Interactions With Drmentioning

confidence: 97%

Determination and modelling of stereoselective interactions of ligands with drug transporters: A key dimension in the understanding of drug disposition

et al. 2008

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Stereochemistry is an important dimension in pharmacology and plays a role in every aspect of the pharmacological fate of chiral xenobiotics. This includes small molecule–drug transporter binding. This paper reviews the reported stereoselectivities of substrate and inhibitor interactions with P-glycoprotein and the organic cation transporter obtained using standard functional and binding studies, as well as data obtained from online cellular membrane affinity chromatography studies. The use of stereochemical data in quantitative structure–activity relationship (QSAR) and pharmacophore modelling is also addressed as is the effect of ignoring the fact that small molecule–drug transporter interactions take place in three-dimensional and asymmetric space.

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Interactions of racemic mefloquine and its enantiomers with P-glycoprotein in an immortalised rat brain capillary endothelial cell line, GPNT

Cited by 69 publications

References 23 publications

Role of P Glycoprotein in Absorption of Novel Antimalarial Drugs

Role of P Glycoprotein in Absorption of Novel Antimalarial Drugs

Mefloquine Induces Dose-Related Neurological Effects in a Rat Model

Determination and modelling of stereoselective interactions of ligands with drug transporters: A key dimension in the understanding of drug disposition

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