Limited<i>P</i>-glycoprotein mediated efflux for anti-epileptic drugs

Crowe, Andrew; Teoh, Yee-Khuan

doi:10.1080/10611860600720814

Cited by 62 publications

(38 citation statements)

References 46 publications

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“…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)(4)(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.…”

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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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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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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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“…The findings by Tishler et al were confirmed by other groups (Dombrowski et al, 2001;Lazarowski et al, 1999;Sisodiya et al, 2002) and it was suggested that this phenomenon could prevent AEDs from entering the brain and cause AED resistance. However, studies in cell lines of non-brain endothelial origin showed that some AEDs such as vigabatrin, gabapentin, phenobarbitone, lamotrigine, carbamazepine, and phenytoin are not, or are only weak, P-gp substrates, questioning whether P-gp could be the primary reason for AED resistance (Crowe & Teoh, 2006;Maines et al, 2005;Owen et al, 2001;Weiss et al, 2003). In contrast, Cucullo et al, compared phenytoin permeation in brain capillary endothelial cells from drug-resistant epileptic human brain tissue with that of commercially available human brain microvascular endothelial cells (Cucullo et al, 2007).…”

Section: Transporters In Epilepsymentioning

confidence: 99%

The Blood-Brain Barrier in Epilepsy

Bauer¹,

Schlichtiger²,

Pekcec³

et al. 2011

Clinical and Genetic Aspects of Epilepsy

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“…The inhibitors included the P-gp inhibitors PSC-833 (4 μM) or GF120918 (4 μM), as used previously (21). The general MRP inhibitor probenecid (at 500 μM) was also used.…”

Section: P-gp and Other Transport Inhibitionmentioning

confidence: 99%

“…Caco-2 sub clone cells, highly expressing P-gp, were seeded onto Millicell polycarbonate 0.6 cm 2 filter inserts in 24-well plates at 65,000 cells/cm 2 , as described previously (21). Cells were grown in 'growth medium' [high glucose DMEM with 25 mM HEPES (pH 7.4), 2 mM glutamine, 1 mM non-essential amino acids, 100 U/mL penicillin-streptomycin, and 10% FCS] in a 37°C incubator with 5% CO 2 .…”

Section: Cell Culturementioning

confidence: 99%

Inhibition of P-glycoprotein–Mediated Efflux of Digoxin and Its Metabolites by Macrolide Antibiotics

Hughes

Crowe

2010

J Pharmacol Sci

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Abstract. This study was conducted to determine the rate of P-glycoprotein (P-gp)-mediated efflux of digoxin analogues and metabolites and to assess the effects of macrolide antibiotics on this efflux. Bidirectional transport studies were conducted using our Caco-2 sub clone with high P-gp expression (CLEFF9). HPLC methods were employed to measure drug transport. All digoxin metabolites were P-gp substrates, although digoxin had the greatest efflux ratio. Erythromycin had no effect on the transport of digoxin, maintaining a basolateral to apical efflux ratio of 14.8, although it did reduce the efflux ratio of dihydrodigoxin and digoxigenin by 34% and 43%, respectively. Azithromycin also had little effect on the transport of digoxin or any of its metabolites. In contrast, clarithromycin and roxithromycin almost eliminated basolateral targeted efflux. Using paclitaxel as a known P-gp substrate, erythromycin demonstrated only partial P-gp inhibitory capacity, maintaining an efflux ratio over 100. In contrast, clarithromycin and roxithromycin were 10-fold greater P-gp inhibitors. Clarithromycin and roxithromycin are likely to exhibit drug interactions with digoxin via inhibition of efflux mechanisms. Azithromycin appears to have little influence on P-gp-mediated digoxin absorption or excretion and would be the safest macrolide to use concurrently with oral digoxin.

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LimitedP-glycoprotein mediated efflux for anti-epileptic drugs

Cited by 62 publications

References 46 publications

Role of P Glycoprotein in Absorption of Novel Antimalarial Drugs

Role of P Glycoprotein in Absorption of Novel Antimalarial Drugs

The Blood-Brain Barrier in Epilepsy

Inhibition of P-glycoprotein–Mediated Efflux of Digoxin and Its Metabolites by Macrolide Antibiotics

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