The potential inhibitory effect of antiparasitic drugs and natural products on P-glycoprotein mediated efflux

Hayeshi, Rose; Masimirembwa, Collen; Mukanganyama, Stanley; Ungell, Anna‐Lena

doi:10.1016/j.ejps.2006.05.009

Cited by 105 publications

(86 citation statements)

References 48 publications

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“…This observation confirms previous reports that showed an inhibitory effect of ADQ against P-gp-mediated transport in Caco-2 cells, as well as an inhibitory effect of ART in K562/adr and GLC4/adr resistant cell lines. 19,20 Next, the impact of ART, ADQ, and LUM on DIG transport was evaluated. In this study, all three antimalarials inhibited DIG transport at concentrations of both 100 μM and 1 mM.…”

Section: Discussionmentioning

confidence: 99%

Potential P-Glycoprotein-Mediated Drug-Drug Interactions of Antimalarial Agents in Caco-2 cells

Oga

Sekine²,

Shitara³

et al. 2012

The American Journal of Tropical Medicine and Hygiene

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Abstract. Antimalarials are widely used in African and Southeast Asian countries, where they are combined with other drugs for the treatment of concurrent ailments. The potential for P-glycoprotein (P-gp)-mediated drug-drug interactions (DDIs) between antimalarials and P-gp substrates was examined using a Caco-2 cell-based model. Selected antimalarials were initially screened for their interaction with P-gp based on the inhibition of rhodamine-123 (Rho-123) transport in Caco-2 cells. Verapamil (100 μM) and quinidine (1 μM) were used as positive inhibition controls. Lumefantrine, amodiaquin, and artesunate all showed blockade of Rho-123 transport. Subsequently, the inhibitory effect of these antimalarials on the bi-directional passage of digoxin (DIG) was examined. All of the drugs decreased basal-toapical (B-A) P-gp-mediated DIG transport at concentrations of 100 μM and 1 mM. These concentrations may reflect therapeutic doses for amodiaquin and artesunate. Therefore, clinically relevant DDIs may occur between certain antimalarials and P-gp substrates in general.

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Section: Discussionmentioning

confidence: 99%

Potential P-Glycoprotein-Mediated Drug-Drug Interactions of Antimalarial Agents in Caco-2 cells

Oga

Sekine²,

Shitara³

et al. 2012

The American Journal of Tropical Medicine and Hygiene

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“…Our observations that QN inhibits glucose uptake in vivo in yeast suggest that this compound might have an antimalarial effect due to inhibition of PfHT1, with the consequent deprivation of the parasite of glucose. Interestingly, a similar substrate and inhibitory role of QN has already been described by several authors for the P. falciparum drug pump encoded by the PfMDR1 gene (18,42). We conclude that PfHT1 is an interesting candidate target of QN, and this working hypothesis is considered to be worth testing in Plasmodium studies.…”

Section: Discussionmentioning

confidence: 73%

“…However, recent studies have demonstrated that this passive transport across the plasma membrane can make up only a small fraction of the drug accumulated by Plasmodium parasites, suggesting that a carrier-mediated import system is probably involved (43). Interestingly, QN has been shown to be both a substrate and an inhibitor of the human multidrug efflux pump P glycoprotein and of its P. falciparum homologue, the PfMDR1 gene product (18,42).…”

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confidence: 99%

Transcriptomic Profiling of theSaccharomyces cerevisiaeResponse to Quinine Reveals a Glucose Limitation Response Attributable to Drug-Induced Inhibition of Glucose Uptake

Santos

Tenreiro

Palma

et al. 2009

Antimicrob Agents Chemother

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Quinine has been employed in the treatment of malaria for centuries and is still used against severe Plasmodium falciparum malaria. However, its interactions with the parasite remain poorly understood and subject to debate. In this study, we used the Saccharomyces cerevisiae eukaryotic model to better understand quinine's mode of action and the mechanisms underlying the cell response to the drug. We obtained a transcriptomic profile of the yeast's early response to quinine, evidencing a marked activation of genes involved in the low-glucose response (e.g., CAT8, ADR1, MAL33, MTH1, and SNF3). We used a low inhibitory quinine concentration with no detectable effect on plasma membrane function, consistent with the absence of a general nutrient starvation response and suggesting that quinine-induced glucose limitation is a specific response. We have further shown that transport of [ 14 C]glucose is inhibited by quinine, with kinetic data indicating competitive inhibition. Also, tested mutant strains deleted for genes encoding high-and low-affinity hexose transporters (HXT1 to HXT5, HXT8, and HXT10) exhibit resistance phenotypes, correlating with reduced levels of quinine accumulation in the mutants examined. These results suggest that the hexose transporters are facilitators of quinine uptake in S. cerevisiae, possibly through a competitive inhibition mechanism. Interestingly, P. falciparum is highly dependent on glucose uptake, which is mediated by the single-copy transporter PfHT1, a protein with high homology to yeast's hexose transporters. We propose that PfHT1 is an interesting candidate quinine target possibly involved in quinine import in P. falciparum, an uptake mechanism postulated in recent studies to occur through a still-unidentified importer(s).

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“…chloroquine) and CYP inducers (e.g. rifampin) [39,40]. Serum level may be increased by cytochrome P450 inhibitors, such as ketoconazole and grapefruit juice [39].…”

Section: Treatmentmentioning

confidence: 99%

Urinary schistosomiasis

Bamgbola

2014

Pediatr Nephrol

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The potential inhibitory effect of antiparasitic drugs and natural products on P-glycoprotein mediated efflux

Cited by 105 publications

References 48 publications

Potential P-Glycoprotein-Mediated Drug-Drug Interactions of Antimalarial Agents in Caco-2 cells

Potential P-Glycoprotein-Mediated Drug-Drug Interactions of Antimalarial Agents in Caco-2 cells

Transcriptomic Profiling of theSaccharomyces cerevisiaeResponse to Quinine Reveals a Glucose Limitation Response Attributable to Drug-Induced Inhibition of Glucose Uptake

Urinary schistosomiasis

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