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 Elacridar

  

Description of Elacridar:   Elacridar hydrochloride (GF120918A) is a  P-glycoprotein inhibitor, and has been used both in vitro and in vivo as a tool inhibitor of P-glycoprotein (Pgp) to investigate the role of transporters in the disposition of various test molecules.  In vitro, GF120918A demonstrated high plasma protein binding across species, although a definitive protein binding evaluation was precluded by poor recovery, particularly in buffer and in mouse, rat, and dog plasma. GF120918A did not demonstrate potent inhibition of several human cytochrome P450 enzymes evaluated in vitro, with IC(50) values well above concentrations anticipated to be achieved in vivo. Together, these data confirm the utility of GF120918A as a tool P-glycoprotein inhibitor in preclinical species and offer additional guidance on preclinical dose regimens likely to produce P-glycoprotein-mediated effects.

     

MedKoo Cat#: 201190

Name: Elacridar hydrochloride

CAS#: 143664-11-3 (free base), 143851-98-3 (elacridar hydrochloride)

  

Synonym:  GF120918;GG 918;Elacridar hydrochloride (USAN);GF-120918A;D03968;

  

IUPAC/Chemical name: 

N-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)phenyl)-5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxamide hydrochloride。

 

Chemical structure:

Theoretical analysis:

 

 

 

  

MedKoo Cat#: 201190
Name: Elacridar hydrochloride
CAS#: 143851-98-3

Elacridar hydrochloride (salt form)

Chemical Formula: C34H34ClN3O5

Molecular Weight: 600.10

Elemental Analysis: C, 68.05; H, 5.71; Cl, 5.91; N, 7.00; O, 13.33

  

Elacridar (free base from)

Chemical Formula: C34H33N3O5

Exact Mass: 563.24202

Molecular Weight: 563.64

Elemental Analysis: C, 72.45; H, 5.90; N, 7.46; O, 14.19

  

  

Availability and price:

Elacridar HCl (99%) is in stock. Quality confirmed by H1-NMR, C13-NMR, HPLC, LC-MS. Price reduced on 12/06/2013.  Delivery time: overnight (USA/Canada), 3-5 days (international).  Shipping fee: $30.00 (USA); $45.00 (Canada); $70.00 (international).

10 mg / $95.00

25 mg / $170.00

50 mg / $310.00

100 mg / $550.00

200 mg / $850.00

500 mg / $1,350.00

1.0 g / $1,950.00

2.0 g / $3,350.00

5.0 g / ask price

Kilograms available at low price.

Also see other P-glycoprotein inhibitor: Elacridar; Tariquidar; Zosuquidar.

 

 

Technical data

Product data sheet

View product data sheet

Appearance:

Yellow solid powder

Purity:

>98% (or refer to the Certificate of Analysis)

Certificate of Analysis:

View current batch of CoA

QC data:

View NMR, View HPLC, View MS

Safety Data Sheet (MSDS):

View Material Safety Data Sheet (MSDS)

Shipping condition:

Shipped under ambient temperature as non-hazardous chemical.  This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage condition:

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility:

Soluble in DMSO, not in water

Shelf life:

>2 years if stored properly

Note: The technical data provided above is for guidance only. For batch specific data refer to the Certificate of Analysis.

 

Protocols from literature

Drug formulation:

This drug may be formulated in DMSO

Stock solution storage:

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

In vitro protocol:

 

In vivo protocol:

 

 

Information about this agent

Phase I combined study of topotecan with Ellacridar: In part I, 20 patients were randomized to receive 100, 300, 500, 700, or 1,000 mg of elacridar on days 1 and 8 1 h before or simultaneously with 2.0 mg oral topotecan, which was also randomized. On day 15, all patients were treated with 1.5 mg/m(2) i.v. topotecan. In part II of the study, patients were treated daily with oral topotecan and with the lowest effective dose of elacridar following from part I. The maximum tolerated dose and dose-limiting toxicity were determined in cohorts of three patients. Blood samples were taken on days 1, 8, and 15 of part I and on day 1 of cycles 1 and 2 of part II. Complete apparent oral bioavailability of topotecan (102 +/- 7%) for all treatment arms with elacridar in both schedules was seen in part I. In the topotecan dose escalation part, two dose-limiting toxicities were seen at the 2.5 mg topotecan dose level.  CONCLUSION:  The recommended schedule is 2.0 mg oral topotecan plus 100 mg elacridar administered concomitantly daily times five every 21 days. (source: Clin Cancer Res. 2007 Jun 1;13(11):3276-85.).

References:

1: Sane R, Agarwal S, Mittapalli RK, Elmquist W. Saturable active efflux by P-gp and Bcrp at the blood-brain barrier leads to non-linear distribution of elacridar to the central nervous system. J Pharmacol Exp Ther. 2013 Feb 8. [Epub ahead of print] PubMed PMID: 23397054.

2: Sane R, Mittapalli RK, Elmquist WF. Development and evaluation of a novel microemulsion formulation of elacridar to improve its bioavailability. J Pharm Sci. 2013 Jan 18. doi: 10.1002/jps.23450. [Epub ahead of print] PubMed PMID: 23334925.

3: Bankstahl JP, Bankstahl M, Romermann K, Wanek T, Stanek J, Windhorst AD, Fedrowitz M, Erker T, Muller M, Loscher W, Langer O, Kuntner C. Tariquidar and Elacridar Are Dose-Dependently Transported by P-Glycoprotein and Bcrp at the Blood-Brain Barrier: A Small-Animal PET and In-Vitro Study. Drug Metab Dispos. 2013 Jan 10. [Epub ahead of print] PubMed PMID: 23305710.

4: Kallem R, Kulkarni CP, Patel D, Thakur M, Sinz M, Singh SP, Mahammad SS, Mandlekar S. A simplified protocol employing elacridar in rodents: a screening model in drug discovery to assess P-gp mediated efflux at the blood brain barrier. Drug Metab Lett. 2012 Jun 1;6(2):134-44. PubMed PMID: 23061481.

5: Sarisozen C, Vural I, Levchenko T, Hincal AA, Torchilin VP. Long-circulating PEG-PE micelles co-loaded with paclitaxel and elacridar (GG918) overcome multidrug resistance. Drug Deliv. 2012 Nov;19(8):363-70. doi: 10.3109/10717544.2012.724473. Epub 2012 Oct 3. PubMed PMID: 23030458.

6: Durmus S, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH. Oral availability and brain penetration of the B-RAFV600E inhibitor vemurafenib can be enhanced by the P-GLYCOprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Mol Pharm. 2012 Nov 5;9(11):3236-45. doi: 10.1021/mp3003144. Epub 2012 Oct 18. PubMed PMID: 23020847.

7: Sane R, Agarwal S, Elmquist WF. Brain distribution and bioavailability of elacridar after different routes of administration in the mouse. Drug Metab Dispos. 2012 Aug;40(8):1612-9. doi: 10.1124/dmd.112.045930. Epub 2012 May 18. PubMed PMID: 22611067; PubMed Central PMCID: PMC3400790.

8: Wanek T, Kuntner C, Bankstahl JP, Bankstahl M, Stanek J, Sauberer M, Mairinger S, Strommer S, Wacheck V, Löscher W, Erker T, Müller M, Langer O. A comparative small-animal PET evaluation of [11C]tariquidar, [11C]elacridar and (R)-[11C]verapamil for detection of P-glycoprotein-expressing murine breast cancer. Eur J Nucl Med Mol Imaging. 2012 Jan;39(1):149-59. doi: 10.1007/s00259-011-1941-7. Epub 2011 Oct 8. PubMed PMID: 21983837.

9: 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. 2012 Jan 1;130(1):223-33. doi: 10.1002/ijc.26000. Epub 2011 Apr 7. PubMed PMID: 21351087.

10: Kuntner C, Bankstahl JP, Bankstahl M, Stanek J, Wanek T, Stundner G, Karch R, Brauner R, Meier M, Ding X, Müller M, Löscher W, Langer O. Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[(11)C]verapamil PET. Eur J Nucl Med Mol Imaging. 2010 May;37(5):942-53. doi: 10.1007/s00259-009-1332-5. Epub 2009 Dec 17. PubMed PMID: 20016890.

11: Dörner B, Kuntner C, Bankstahl JP, Bankstahl M, Stanek J, Wanek T, Stundner G, Mairinger S, Löscher W, Müller M, Langer O, Erker T. Synthesis and small-animal positron emission tomography evaluation of [11C]-elacridar as a radiotracer to assess the distribution of P-glycoprotein at the blood-brain barrier. J Med Chem. 2009 Oct 8;52(19):6073-82. doi: 10.1021/jm900940f. PubMed PMID: 19711894.

12: Lagas JS, van Waterschoot RA, van Tilburg VA, Hillebrand MJ, Lankheet N, Rosing H, Beijnen JH, Schinkel AH. Brain accumulation of dasatinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by elacridar treatment. Clin Cancer Res. 2009 Apr 1;15(7):2344-51. doi: 10.1158/1078-0432.CCR-08-2253. Epub 2009 Mar 10. PubMed PMID: 19276246.

13: Hubensack M, Müller C, Höcherl P, Fellner S, Spruss T, Bernhardt G, Buschauer A. Effect of the ABCB1 modulators elacridar and tariquidar on the distribution of paclitaxel in nude mice. J Cancer Res Clin Oncol. 2008 May;134(5):597-607. Epub 2007 Oct 12. PubMed PMID: 17932689.

14: Kuppens IE, Witteveen EO, Jewell RC, Radema SA, Paul EM, Mangum SG, Beijnen JH, Voest EE, Schellens JH. A phase I, randomized, open-label, parallel-cohort, dose-finding study of elacridar (GF120918) and oral topotecan in cancer patients. Clin Cancer Res. 2007 Jun 1;13(11):3276-85. PubMed PMID: 17545533.

15: Bihorel S, Camenisch G, Lemaire M, Scherrmann JM. Modulation of the brain distribution of imatinib and its metabolites in mice by valspodar, zosuquidar and elacridar. Pharm Res. 2007 Sep;24(9):1720-8. Epub 2007 Mar 23. PubMed PMID: 17380257.

16: Wong HL, Bendayan R, Rauth AM, Wu XY. Simultaneous delivery of doxorubicin and GG918 (Elacridar) by new polymer-lipid hybrid nanoparticles (PLN) for enhanced treatment of multidrug-resistant breast cancer. J Control Release. 2006 Dec 1;116(3):275-84. Epub 2006 Sep 26. PubMed PMID: 17097178.

17: Stokvis E, Rosing H, Causon RC, Schellens JH, Beijnen JH. Quantitative analysis of the P-glycoprotein inhibitor Elacridar (GF120918) in human and dog plasma using liquid chromatography with tandem mass spectrometric detection. J Mass Spectrom. 2004 Oct;39(10):1122-30. PubMed PMID: 15468145.

18: Barraud de Lagerie S, Comets E, Gautrand C, Fernandez C, Auchere D, Singlas E, Mentre F, Gimenez F. Cerebral uptake of mefloquine enantiomers with and without the P-gp inhibitor elacridar (GF1210918) in mice. Br J Pharmacol. 2004 Apr;141(7):1214-22. Epub 2004 Mar 15. PubMed PMID: 15023856; PubMed Central PMCID: PMC1574889.  

   

 

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