P-glycoprotein inhibitors and their screening: a perspective from bioavailability enhancement

Varma, Manthena V.; Ashokraj, Yasvanth; Dey, Chinmoy Sankar; Panchagnula, Ramesh

doi:10.1016/s1043-6618(03)00158-0

Cited by 356 publications

(220 citation statements)

References 52 publications

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“…P-glycoprotein inhibitors influences metabolism, absorption, distribution, and elimination of P-glycoprotein substrates in the process of modulating pharmacokinetics [21] .…”

Section: P-glycoprotein Inhibitorsmentioning

confidence: 99%

Bioavailability enhancers of herbal origin: An overview

Kesarwani

Gupta

2013

Asian Pacific Journal of Tropical Biomedicine

397

197

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“…P-glycoprotein inhibitors influences metabolism, absorption, distribution, and elimination of P-glycoprotein substrates in the process of modulating pharmacokinetics [21] .…”

Section: P-glycoprotein Inhibitorsmentioning

confidence: 99%

Bioavailability enhancers of herbal origin: An overview

Kesarwani

Gupta

2013

Asian Pacific Journal of Tropical Biomedicine

397

197

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“…As P-glycoprotein binds many different hydrophobic compounds, a large number of treatments have been described, which inhibit P-glycoprotein activity either by blocking drug binding, by interfering with ATP hydrolysis, or by altering the integrity of cell membrane lipids (13). In parallel, fatty acid ester surfactants, including Cremophor-EL, Triton X-100, and Tween 80, have been shown to interact with P-glycoprotein and to revert MDR (13). However, the use of most of these compounds is limited by their toxicity due to the high serum concentration that is required to inhibit P-glycoprotein.…”

Section: Introductionmentioning

confidence: 99%

A new generation of anticancer, drug-loaded, colloidal vectors reverses multidrug resistance in glioma and reduces tumor progression in rats

Garcion

Lamprecht

Heurtault

et al. 2006

Molecular Cancer Therapeutics

172

107

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By focusing on rat glioma, we elucidated whether new lipid nanocapsules (LNC) were able to improve anticancer hydrophobic drug bioavailability while also overcoming multidrug resistance. Blank LNCs and LNCs loaded with the antineoplastic agent paclitaxel were formulated by an emulsion inversion phase process. Expression of efflux pumps by rat glioma cells was assessed by reverse transcription-PCR, Western blot, and immunohistochemistry, and their activity was followed using the tracer 99 Tc m -methoxyisobutylisonitrile. Modalities of LNC action were addressed by using confocal microscopy detection of fluorescently labeled LNCs, fluorescence-activated cell sorting, high-performance liquid chromatography measurement of paclitaxel release, and analysis of tumor cell growth. This revealed an interaction between LNCs and efflux pumps that resulted in an inhibition of multidrug resistance in glioma cells, both in culture and in cell implants in animals. LNCs were able to target the intracellular compartment of glioma cells, a mechanism that was abrogated by using intracellular cholesterol inhibitors but not by clathrin-coated pit or caveolae uptake inhibitors. This result can be correlated to the LNC inhibitory effects on efflux pump activity that is itself known to be stimulated by intracellular cholesterol. In parallel, we showed that paclitaxel-loaded LNCs were active reservoirs from which paclitaxel could be released. Finally, we established that paclitaxel-loaded LNCs were more efficient than the commercially available paclitaxel formulation (Taxol) for clinical use, thus reducing tumor expansion in vitro and in vivo. Considering the physiologically compatible nature of LNC excipients, these data may represent an important step towards the development of new clinical therapeutic strategies against cancers.

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“…P-gp is ubiquitously expressed on human tissues such as intestinal mucosa, brain capillary endothelial cells, biliary canaliculus, and kidney tubules (Thiebaut et al, 1987). Broad substrate specificity of P-gp is a major factor responsible for subtherapeutic levels of various drugs in blood and tissues (Varma et al, 2003). A recent report suggests that presence of this efflux transporter on the brush border membrane of intestinal epithelium not only diminishes permeability of various therapeutic agents but also enhances the metabolism of these molecules by effluxing the drugs into the intestinal lumen or blood capillaries thereby increasing drug exposure to cellular as well as lumenal enzymes (Lown et al, 1997;Watkins, 1997;Ito et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Intestinal absorption of novel-dipeptide prodrugs of saquinavir in rats

Jain

Duvvuri

Kansara

et al. 2007

International Journal of Pharmaceutics

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Saquinavir (SQV) was the first human immuno-virus-1 (HIV-1) protease inhibitor approved by FDA. However, P-glycoprotein (P-gp), an efflux pump limits its oral and brain bioavailabilities. The objective of this study is to investigate whether prodrug modification of SQV to dipeptide prodrugs Valine-Valine-Saquinavir (Val-Val-SQV) and Glycine-Valine-Saquinavir (Gly-Val-SQV) targeting intestinal peptide transporter can enhance intestinal permeability of SQV by circumventing P-gp mediated efflux. Single pass intestinal perfusion experiments in rat jejunum were performed to calculate the absorption rate constant and intestinal permeability of SQV, ValVal-SQV and Gly-Val-SQV. Equimolar concentration (25 μM) of SQV, Val-Val-SQV and GlyVal-SQV were employed in the perfusion studies. Perfusion experiments were also carried out in the presence of cyclosporine (10 μM) and glycyl-sarcosine (20mM). Absorption rate constants in rat jejunum (k a ) for SQV, Val-Val-SQV and Gly-Val-SQV were found to be 14.1±3.4 ×10 −3 , 65.8±4.3 ×10 −3 , and 25.6±5.7 ×10 −3 min −1 respectively. Enhanced absorption of Val-Val-SQV and Gly-Val-SQV relative to SQV can be attributed to their translocation by the peptide transporter in the jejunum. Significant permeability enhancement of SQV across rat jejunum was observed in the presence of cyclosporine 10 μM (P-gp inhibitor). However, permeability of ValVal-SQV was unchanged in the presence of cyclosporine suggesting lack of any interaction of the prodrug with efflux pump. Intestinal absorption of Val-Val-SQV was significantly inhibited in the presence of gly-sar indicating the involvement of peptide transporter in intestinal absorption. In conclusion, peptide transporter targeted prodrug modification of P-gp substrates could lead to shielding of these drug molecules from efflux pumps.

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P-glycoprotein inhibitors and their screening: a perspective from bioavailability enhancement

Cited by 356 publications

References 52 publications

Bioavailability enhancers of herbal origin: An overview

Bioavailability enhancers of herbal origin: An overview

A new generation of anticancer, drug-loaded, colloidal vectors reverses multidrug resistance in glioma and reduces tumor progression in rats

Intestinal absorption of novel-dipeptide prodrugs of saquinavir in rats

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