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Elacridar

BCRP inhibitor CAS# 143664-11-3

Elacridar

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Chemical structure

Elacridar

3D structure

Chemical Properties of Elacridar

Cas No. 143664-11-3 SDF Download SDF
PubChem ID 119373 Appearance Powder
Formula C34H33N3O5 M.Wt 563.64
Type of Compound N/A Storage Desiccate at -20°C
Synonyms GF120918; GW0918; GG918; GW120918
Solubility DMSO : 5 mg/mL (8.87 mM; Need ultrasonic)
H2O : < 0.1 mg/mL (insoluble)
Chemical Name N-[4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]-5-methoxy-9-oxo-10H-acridine-4-carboxamide
SMILES COC1=CC=CC2=C1NC3=C(C2=O)C=CC=C3C(=O)NC4=CC=C(C=C4)CCN5CCC6=CC(=C(C=C6C5)OC)OC
Standard InChIKey OSFCMRGOZNQUSW-UHFFFAOYSA-N
Standard InChI InChI=1S/C34H33N3O5/c1-40-28-9-5-7-26-32(28)36-31-25(33(26)38)6-4-8-27(31)34(39)35-24-12-10-21(11-13-24)14-16-37-17-15-22-18-29(41-2)30(42-3)19-23(22)20-37/h4-13,18-19H,14-17,20H2,1-3H3,(H,35,39)(H,36,38)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Elacridar

DescriptionElacridar (GF120918; GW0918) is an inhibitor of P-glycoprotein.
TargetsP-glycoprotein    

Protocol

Kinase Assay [2]
10 μL of unlabeled cell membrane suspension (at 0.4 mg of protein/mL) are aliquoted into each well in 96-well plates. 5 μL of GF120918 are then added to each well. The plate is incubated 25 min at 25°C in the dark. 5 μL of tritiated azidopine (1.8 TBq/mmol) (0.6 μM in HCI 0.2 mM) are added to each well. After 25 min of incubation at 25°C in the dark, samples are simultaneously irradiated for 2 min at 254 nm at 0°C with a thin layer chromatography-designed UV lamp directly in contact with the plate. Samples are solubilized in sodium dodecyl sulfate-polyacrylamide gel electrophoresis sample buffer but not heated. After separation on a 7.5% polyacrylamide gel, the gel is treated for fluorography with Amplify and exposed during 3 days onto a photosensitive film. The fluorography is analysed using a Camag thin layer chromatography Scanner II densitometer.

Cell Assay [3]
3.0×103 cells per well are seeded in a 96-well plate. After 24 h incubation, an optimum concentration gradient of elacridar is added to each well. After culturing for 48 h, cell viability is assessed using the proliferation reagent, MTT. Control cells are treated with the vehicle only, 0.1% DMSO. After this final incubation, the medium is aspirated and precipitated formazan crystals are dissolved in DMSO (100 μL/well). The absorbance of each well is measured at 540 nm, and a reference wavelength of 650 nm is read with a multiskan JX microplate reader. Cell viability is calculated as percentage of the control value[3].

Animal Administration [1]
Mice are fasted for 3 hr before oral administration of either elacridar (100 mg/kg) or elacridar vehicle. Two hours later, crizotinib (5 mg/kg) is administered to mice orally. Blood and brains are isolated 4 hr after crizotinib oral administration, and processed as described above. The brain concentrations are corrected for the amount of drug in the brain vasculature. Elacridar hydrochloride is dissolved in dimethyl sulfoxide (106 mg/mL) in order to get 100 mg pure elacridar per 1 mL of dimethyl sulfoxide. The stock solution is further diluted with a mixture of Polysorbate 80, ethanol and water [20:13:67 (v/v/v)] to yield a concentration of 10 mg/mL pure elacridar.

References:
[1]. Tang SC, et al. Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Int J Cancer. 2014 Mar 15;134(6):1484-94 [2]. Hyafil F, et al. In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative. Cancer Res. 1993 Oct 1;53(19):4595-602. [3]. Sato H, et al. Elacridar enhances the cytotoxic effects of sunitinib and prevents multidrug resistance in renal carcinoma cells. Eur J Pharmacol. 2015 Jan 5;746:258-66. [4]. Sane R, et al. Brain distribution and bioavailability of elacridar after different routes of administration in the mouse. Drug Metab Dispos. 2012 Aug;40(8):1612-9. [5]. de Vries NA, et al. P-glycoprotein and breast cancer resistance protein: two dominant transporters working together in limiting the brain penetration of topotecan. Clin Cancer Res. 2007 Nov 1;13(21):6440-9.

Elacridar Dilution Calculator

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Preparing Stock Solutions of Elacridar

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.7742 mL 8.8709 mL 17.7418 mL 35.4836 mL 44.3546 mL
5 mM 0.3548 mL 1.7742 mL 3.5484 mL 7.0967 mL 8.8709 mL
10 mM 0.1774 mL 0.8871 mL 1.7742 mL 3.5484 mL 4.4355 mL
50 mM 0.0355 mL 0.1774 mL 0.3548 mL 0.7097 mL 0.8871 mL
100 mM 0.0177 mL 0.0887 mL 0.1774 mL 0.3548 mL 0.4435 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Elacridar

Elacridar is a potent inhibitor of P-glycoprotein with IC50 values of 193 nM. [1]

P-glycoprotein (permeability glycoprotein) is an important membrane protein. It pumps many foreign substances out of cells. P-glycoprotein belongs to the MDR/TAP subfamily. P-glycoprotein is transmembrane glycoprotein which is about 170 kDa. It is expressed in certain cell types primarily in the pancreas, liver, colon and kidney. It contains 6 transmembrane domains in the N-terminal half of the molecule. It also contains an ATP-binding site in the large cytoplasmic domain. P-glycoprotein binds to the substrate at the cytoplasmic side of the protein. When ATP binds to the cytoplasmic side, the substrate was excreted from the cell. P-glycoprotein can pump toxins or drugs back into the intestinal lumen, pumps them into bile ducts in liver cells.In some cancer cells, P-glycoprotein is overexpressed. It is involved in multidrug resistance of cancer cells.[2]

Elacridar can significantly inhibit the activity of P-glycoprotein at 1μM in MDCKII cells which overexpress P-glycoprotein.[3] In the parental MDCK-II cells, elacridar at 5μM completely inhibit the polarized sunitinib transport.[4] Elacridar did not inhibit the activity of several human cytochromeP450 enzymes in vitro. The absolute bioavailability was about 0.47 and 1.3 respectively, when elacridar was given in the orally and microemulsion, intraperitoneally at 10 mg/kg in mice.[3] Elacridar also can significantly increase sunitinib brain accumulation levels in mice at 10 mg/kg.[4]

References:
[1].  Bankstahl JP, Bankstahl M, Romermann K, Wanek T, Stanek J, Windhorst AD, Fedrowitz M, Erker T, Muller M, Loscher W et al: Tariquidar and elacridar are dose-dependently transported by P-glycoprotein and Bcrp at the blood-brain barrier: a small-animal positron emission tomography and in vitro study. Drug Metab Dispos, 41(4):754-762.
[2].  Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT, Zhang Q, Urbatsch IL et al: Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 2009, 323(5922):1718-1722.
[3].  Sane R, Mittapalli RK, Elmquist WF: Development and evaluation of a novel microemulsion formulation of elacridar to improve its bioavailability. J Pharm Sci, 102(4):1343-1354.
[4].  Tang SC, Lagas JS, Lankheet NA, Poller B, Hillebrand MJ, Rosing H, Beijnen JH, Schinkel AH: Brain accumulation of sunitinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by oral elacridar and sunitinib coadministration. Int J Cancer, 130(1):223-233.

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References on Elacridar

Whole-Body Distribution and Radiation Dosimetry of 11C-Elacridar and 11C-Tariquidar in Humans.[Pubmed:27081167]

J Nucl Med. 2016 Aug;57(8):1265-8.

UNLABELLED: (11)C-Elacridar and (11)C-tariquidar are new PET tracers to assess the transport activity of P-glycoprotein (adenosine triphosphate-binding cassette subfamily B, member 1 [ABCB1]) and breast cancer resistance protein (adenosine triphosphate-binding cassette subfamily G, member 2 [ABCG2]). This study investigated the whole-body distribution and radiation dosimetry of both radiotracers in humans. METHODS: Twelve healthy volunteers (6 women, 6 men) underwent whole-body PET/CT imaging over the 90 min after injection of either (11)C-Elacridar or (11)C-tariquidar. Radiation doses were calculated with OLINDA/EXM software using adult reference phantoms. RESULTS: Biodistribution was consistent with a major elimination route of hepatobiliary excretion, which may be mediated by ABCB1 and ABCG2. High radioactivity uptake was seen in liver, followed by spleen and kidneys, whereas brain uptake was lowest. Effective doses were 3.41 +/- 0.06 muSv/MBq for (11)C-elacidar and 3.62 +/- 0.11 muSv/MBq for (11)C-tariquidar. CONCLUSION: Our data indicate that both (11)C-Elacridar and (11)C-tariquidar are safe radiotracers, for which an injected activity of 400 MBq corresponds to a total effective dose of approximately 1.5 mSv.

Liposomes Coloaded with Elacridar and Tariquidar To Modulate the P-Glycoprotein at the Blood-Brain Barrier.[Pubmed:26390138]

Mol Pharm. 2015 Nov 2;12(11):3829-38.

This study prepared three liposomal formulations coloaded with Elacridar and tariquidar to overcome the P-glycoprotein-mediated efflux at the blood-brain barrier. Their pharmacokinetics, brain distribution, and impact on the model P-glycoprotein substrate, loperamide, were compared to those for the coadministration of free Elacridar plus free tariquidar. After intravenous administration in rats, Elacridar and tariquidar in conventional liposomes were rapidly cleared from the bloodstream. Their low levels in the brain did not improve the loperamide brain distribution. Although Elacridar and tariquidar in PEGylated liposomes exhibited 2.6 and 1.9 longer half-lives than free Elacridar and free tariquidar, respectively, neither their Kp for the brain nor the loperamide brain distribution was improved. However, the conjugation of OX26 F(ab')2 fragments to PEGylated liposomes increased the Kps for the brain of Elacridar and tariquidar by 1.4- and 2.1-fold, respectively, in comparison to both free P-gp modulators. Consequently, the Kp for the brain of loperamide increased by 2.7-fold. Moreover, the plasma pharmacokinetic parameters and liver distribution of loperamide were not modified by the PEGylated OX26 F(ab')2 immunoliposomes. Thus, this formulation represents a promising tool for modulating the P-glycoprotein-mediated efflux at the blood-brain barrier and could improve the brain uptake of any P-glycoprotein substrate that is intended to treat central nervous system diseases.

Clinical pharmacokinetics of an amorphous solid dispersion tablet of elacridar.[Pubmed:27864786]

Drug Deliv Transl Res. 2017 Feb;7(1):125-131.

Elacridar is an inhibitor of the permeability glycoprotein (P-gp) and the breast cancer resistance protein (BCRP) and is a promising absorption enhancer of drugs that are substrates of these drug-efflux transporters. However, Elacridar is practically insoluble in water, resulting in low bioavailability which currently limits its clinical application. We evaluated the in vitro dissolution and clinical pharmacokinetics of a novel amorphous solid dispersion (ASD) tablet containing Elacridar. The dissolution from ASD tablets was compared to that from a crystalline powder mixture in a USP type II dissolution apparatus. The pharmacokinetics of the ASD tablet were evaluated in an exploratory clinical study at oral doses of 25, 250, or 1000 mg in 12 healthy volunteers. A target Cmax was set at >/= 200 ng/mL based on previous clinical data. The in vitro dissolution from the ASD tablet was 16.9 +/- 3.7 times higher compared to that from a crystalline powder mixture. Cmax and AUC0-infinity increased linearly with dose over the explored range. The target Cmax of >/= 200 ng/mL was achieved at the 1000-mg dose level. At this dose, the Cmax and AUC0-infinity were 326 +/- 67 ng/mL and 13.4 +/- 8.6 . 10(3) ng . h/mL, respectively. In summary, the ASD tablet was well tolerated, resulted in relevant pharmacokinetic exposure, and can be used for proof-of-concept clinical studies.

Pharmaceutical development of an amorphous solid dispersion formulation of elacridar hydrochloride for proof-of-concept clinical studies.[Pubmed:28010129]

Drug Dev Ind Pharm. 2017 Apr;43(4):584-594.

OBJECTIVE: A novel tablet formulation containing an amorphous solid dispersion (ASD) of Elacridar hydrochloride was developed with the purpose to resolve the drug's low solubility in water and to conduct proof-of-concept clinical studies. SIGNIFICANCE: Elacridar is highly demanded for proof-of-concept clinical trials that study the drug's suitability to boost brain penetration and bioavailability of numerous anticancer agents. Previously, clinical trials with Elacridar were performed with a tablet containing Elacridar hydrochloride. However, this tablet formulation resulted in poor and unpredictable absorption which was caused by the low aqueous solubility of Elacridar hydrochloride. METHODS: Twenty four different ASDs were produced and dissolution was compared to crystalline Elacridar hydrochloride and a crystalline physical mixture. The formulation with highest dissolution was characterized for amorphicity. Subsequently, a tablet was developed and monitored for chemical/physical stability for 12 months at +15-25 degrees C, +2-8 degrees C and -20 degrees C. RESULTS: The ASD powder was composed of freeze dried Elacridar hydrochloride-povidone K30-sodium dodecyl sulfate (1:6:1, w/w/w), appeared fully amorphous and resulted in complete dissolution whereas crystalline Elacridar hydrochloride resulted in only 1% dissolution. The ASD tablets contained 25 mg Elacridar hydrochloride and were stable for at least 12 months at -20 degrees C. CONCLUSIONS: The ASD tablet was considered feasible for proof-of-concept clinical studies and is now used as such.

Description

Elacridar is a potent P-glycoprotein (Pgp) and BCRP inhibitor.

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