Rapid assessment of p-glycoprotein-drug interactions at the blood-brain barrier.
AuthorsBubik M, Ott M, Mahringer A, Fricker G
JournalAnal Biochem
PubMed ID16942742
'We report on a cost- and time-effective fluorescent dye (calcein-acetoxymethylester; calcein-AM)-based assay to screen compounds for p-glycoprotein (p-gp) interactions at the blood-brain barrier. This assay enables the use of freshly isolated or freshly defrosted endothelial cells without prior cell culture. Isolated porcine brain capillary endothelial cells (PBCECs) in suspension were ... More
Quantitative characterization of direct P-glycoprotein inhibition by St John's wort constituents hypericin and hyperforin.
AuthorsWang EJ, Barecki-Roach M, Johnson WW
JournalJ Pharm Pharmacol
PubMed ID14980009
'The ATP-binding cassette transporter P-glycoprotein (P-gp) exerts a critical role in the systemic disposition of, and exposure to, lipophilic and amphipathic drugs, carcinogens, toxins and other xenobiotics. The ability of P-gp to transfer a wide variety of structurally unrelated compounds from the cell interior across the membrane bilayer remains intriguing. ... More
Influence of lipid lowering fibrates on P-glycoprotein activity in vitro.
AuthorsEhrhardt M, Lindenmaier H, Burhenne J, Haefeli WE, Weiss J
JournalBiochem Pharmacol
PubMed ID14698041
'Statin/fibrate combinations are frequently used to treat mixed dyslipidemia. However, these combinations may cause life-threatening drug interactions (e.g. rhabdomyolysis) possibly induced by modifications of cytochrome P450 isozyme activities. Some statins are also transported by P-glycoprotein (Pgp) and may act as inhibitors of this drug efflux pump. So far, nothing is ... More
Differential multidrug resistance-associated protein 1 through 6 isoform expression and function in human intestinal epithelial Caco-2 cells.
AuthorsPrime-Chapman HM, Fearn RA, Cooper AE, Moore V, Hirst BH
JournalJ Pharmacol Exp Ther
PubMed ID15210835
'Multidrug resistance-associated protein (MRP) isoforms 1 through 6 mRNA are expressed in the human intestine and Caco-2 cells. In Caco-2 cells, the rank order for mRNA expression was MRP2 > or = MRP6 > MRP4 > or = MRP3 > MRP1 = MRP5. The functional expression of MRP-like activity was ... More
Multidrug resistance reversal agent, NSC77037, identified with a cell-based screening assay.
AuthorsSusa M, Choy E, Yang C, Schwab J, Mankin H, Hornicek F, Duan Z,
JournalJ Biomol Screen
PubMed ID20150589
'The development of multidrug resistance (MDR) remains a significant obstacle in treating cancer patients with chemotherapy. To identify small-molecule compounds that can reverse MDR, the authors used a cell-based screening assay with an MDR ovarian cancer cell line. Incubating MDR cells with a sublethal concentration of paclitaxel in combination with ... More
Expression of aryl hydrocarbon receptor nuclear translocator enhances cisplatin resistance by upregulating MDR1 expression in cancer cells.
The identification of molecular pathways in cancer cells is important for understanding the cells' underlying biology and for designing effective cancer therapies. We demonstrate that the expression of aryl hydrocarbon receptor nuclear translocator (ARNT) is critical during the development of cisplatin resistance. The reduced expression of ARNT was correlated with ... More
Pharmacokinetic interaction of the antiparasitic agents ivermectin and spinosad in dogs.
AuthorsDunn ST, Hedges L, Sampson KE, Lai Y, Mahabir S, Balogh L, Locuson CW,
JournalDrug Metab Dispos
PubMed ID21321059
Neurological side effects consistent with ivermectin toxicity have been observed in dogs when high doses of the common heartworm prevention agent ivermectin are coadministered with spinosad, an oral flea prevention agent. Based on numerous reports implicating the role of the ATP-binding cassette drug transporter P-glycoprotein (P-gp) in ivermectin efflux in ... More
Regulation and characterization of the ATP-binding cassette transporter-B1 in the epididymis and epididymal spermatozoa of the rat.
AuthorsJones SR, Cyr DG,
JournalToxicol Sci
PubMed ID20961954
It has been reported that following administration, alkylphenols, such as octylphenol, reach the testis and epididymis but fail to accumulate in these tissues, suggesting the rapid expulsion of these chemicals by transporters. Specialized transporters that function to restrict compounds that enter target cells have been identified. ABCB1 is a member ... More
Post-transcriptional regulation of P-glycoprotein expression in cancer cell lines.
AuthorsGómez-Martínez A, García-Morales P, Carrato A, Castro-Galache MD, Soto JL, Carrasco-García E, García-Bautista M, Guaraz P, Ferragut JA, Saceda M,
JournalMol Cancer Res
PubMed ID17579122
The present study of inhibitors shows that the histone deacetylase-induced increase in P-glycoprotein (Pgp) mRNA (MDR1 mRNA) does not parallel either an increase in Pgp protein or an increase in Pgp activity in several colon carcinoma cell lines. Furthermore, studying the polysome profile distribution, we show a translational control of ... More
Overexpression of CD133 promotes drug resistance in C6 glioma cells.
AuthorsAngelastro JM, Lamé MW,
JournalMol Cancer Res
PubMed ID20663862
Glioblastoma multiforme is an extremely aggressive and clinically unresponsive form of cancer. Transformed neoplastic neural stem cells, resistant to chemotherapy and radiation therapy, are thought to be responsible for the initial tumor formation and the recurrence of disease following surgical resection. These stem cells express multidrug resistance markers along with ... More
Pharmacologic inhibition of Pim kinases alters prostate cancer cell growth and resensitizes chemoresistant cells to taxanes.
AuthorsMumenthaler SM, Ng PY, Hodge A, Bearss D, Berk G, Kanekal S, Redkar S, Taverna P, Agus DB, Jain A,
JournalMol Cancer Ther
PubMed ID19825806
The serine/threonine family of Pim kinases function as oncogenes and have been implicated in prostate cancer progression, particularly in hormone-refractory prostate disease, as a result of their antiapoptotic function. In this study, we used a pharmacologic inhibitor targeting the Pim family members, SGI-1776, to determine whether modulation of Pim kinase ... More
Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs.
AuthorsMahar Doan KM, Humphreys JE, Webster LO, Wring SA, Shampine LJ, Serabjit-Singh CJ, Adkison KK, Polli JW,
JournalJ Pharmacol Exp Ther
PubMed ID12438524
Membrane permeability and P-glycoprotein (Pgp) can be limiting factors for blood-brain barrier penetration. The objectives of this study were to determine whether there are differences in the in vitro permeability, Pgp substrate profiles, and physicochemical properties of drugs for central nervous system (CNS) and non-CNS indications, and whether these differences ... More
Inhibition of P-glycoprotein by newer antidepressants.
AuthorsWeiss J, Dormann SM, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, Haefeli WE,
JournalJ Pharmacol Exp Ther
PubMed ID12649369
Pharmacokinetic drug-drug interactions often occur at the level of P-glycoprotein (Pgp). To study possible interactions caused by the newer antidepressants we investigated citalopram, fluoxetine, fluvoxamine, paroxetine, reboxetine, sertraline, and venlafaxine and their major metabolites desmethylcitalopram, norfluoxetine, paroxetine-metabolite (paroxetine-M), desmethylsertraline, N-desmethylvenlafaxine, and O-desmethylvenlafaxine for their ability to inhibit Pgp. Pgp inhibition ... More
Predicting P-glycoprotein substrates by a quantitative structure-activity relationship model.
AuthorsGombar VK, Polli JW, Humphreys JE, Wring SA, Serabjit-Singh CS
JournalJ Pharm Sci
PubMed ID14999732
A quantitative structure-activity relationship (QSAR) model has been developed to predict whether a given compound is a P-glycoprotein (Pgp) substrate or not. The training set consisted of 95 compounds classified as substrates or non-substrates based on the results from in vitro monolayer efflux assays. The two-group linear discriminant model uses ... More
Glutathione export during apoptosis requires functional multidrug resistance-associated proteins.
AuthorsHammond CL, Marchan R, Krance SM, Ballatori N
JournalJ Biol Chem
PubMed ID17374608
GSH is released in cells undergoing apoptosis, and the present study indicates that the multidrug resistance-associated proteins (MRPs/ABCC) are responsible for this GSH release. Jurkat cells released approximately 75-80% of their total intracellular GSH during both Fas antibody- and staurosporine-induced apoptosis. In contrast, Raji cells, a lymphocyte cell line that ... More
In vitro p-glycoprotein inhibition assays for assessment of clinical drug interaction potential of new drug candidates: a recommendation for probe substrates.
AuthorsRautio J, Humphreys JE, Webster LO, Balakrishnan A, Keogh JP, Kunta JR, Serabjit-Singh CJ, Polli JW
JournalDrug Metab Dispos
PubMed ID16455806
Because modulation of P-glycoprotein (Pgp) through inhibition or induction can lead to drug-drug interactions by altering intestinal, central nervous system, renal, or biliary efflux, it is anticipated that information regarding the potential interaction of drug candidates with Pgp will be a future regulatory expectation. Therefore, to be able to utilize ... More