Back to products

Browse products

Approved anticancer agents

Anticancer agents in trials

Anticancer molecular libraries

MedKoo product information:

 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.

Current developer:  GlaxoSmithKline

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.).

1: 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. Epub 2011 Oct 8. PubMed PMID: 21983837.

2: 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.

3: 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. Epub 2009 Dec 17. PubMed PMID: 20016890.

4: 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. PubMed PMID: 19711894.

5: 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. Epub 2009 Mar 10. PubMed PMID: 19276246.

6: 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.

7: 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.

8: 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.

9: 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.

10: 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.

11: 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.

1: Kawamura K, Yamasaki T, Konno F, Yui J, Hatori A, Yanamoto K, Wakizaka H, Ogawa M, Yoshida Y, Nengaki N, Fukumura T, Zhang MR. Synthesis and in vivo evaluation of ¹⁸F-fluoroethyl GF120918 and XR9576 as positron emission tomography probes for assessing the function of drug efflux transporters. Bioorg Med Chem. 2011 Jan 15;19(2):861-70. Epub 2010 Dec 5. PubMed PMID: 21185730.

2: Yamasaki T, Kawamura K, Hatori A, Yui J, Yanamoto K, Yoshida Y, Ogawa M, Nengaki N, Wakisaka H, Fukumura T, Zhang MR. PET study on mice bearing human colon adenocarcinoma cells using [11C]GF120918, a dual radioligand for P-glycoprotein and breast cancer resistance protein. Nucl Med Commun. 2010 Nov;31(11):985-93. PubMed PMID: 20859232.

3: Bottova I, Sauder U, Olivieri V, Hehl AB, Sonda S. The P-glycoprotein inhibitor GF120918 modulates Ca2+-dependent processes and lipid metabolism in Toxoplasma gondii. PLoS One. 2010 Apr 8;5(4):e10062. PubMed PMID: 20386707; PubMed Central PMCID: PMC2851653.

4: Kawamura K, Yamasaki T, Konno F, Yui J, Hatori A, Yanamoto K, Wakizaka H, Takei M, Kimura Y, Fukumura T, Zhang MR. Evaluation of limiting brain penetration related to P-glycoprotein and breast cancer resistance protein using [(11)C]GF120918 by PET in mice. Mol Imaging Biol. 2011 Feb;13(1):152-60. PubMed PMID: 20379788.

5: Wang L, Leggas M, Goswami M, Empey PE, McNamara PJ. N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dih ydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) as a chemical ATP-binding cassette transporter family G member 2 (Abcg2) knockout model to study nitrofurantoin transfer into milk. Drug Metab Dispos. 2008 Dec;36(12):2591-6. Epub 2008 Sep 17. PubMed PMID: 18799806; PubMed Central PMCID: PMC2837273.

6: 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.

7: Planting AS, Sonneveld P, van der Gaast A, Sparreboom A, van der Burg ME, Luyten GP, de Leeuw K, de Boer-Dennert M, Wissel PS, Jewell RC, Paul EM, Purvis NB Jr, Verweij J. A phase I and pharmacologic study of the MDR converter GF120918 in combination with doxorubicin in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2005 Jan;55(1):91-9. Epub 2004 Jul 28. PubMed PMID: 15565444.

8: 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.

9: Ward KW, Azzarano LM. Preclinical pharmacokinetic properties of the P-glycoprotein inhibitor GF120918A (HCl salt of GF120918, 9,10-dihydro-5-methoxy-9-oxo-N-[4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquino linyl)ethyl]phenyl]-4-acridine-carboxamide) in the mouse, rat, dog, and monkey. J Pharmacol Exp Ther. 2004 Aug;310(2):703-9. Epub 2004 Mar 31. PubMed PMID: 15056727.

10: Kruijtzer CM, Beijnen JH, Rosing H, ten Bokkel Huinink WW, Schot M, Jewell RC, Paul EM, Schellens JH. Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J Clin Oncol. 2002 Jul 1;20(13):2943-50. PubMed PMID: 12089223.

11: Edwards JE, Brouwer KR, McNamara PJ. GF120918, a P-glycoprotein modulator, increases the concentration of unbound amprenavir in the central nervous system in rats. Antimicrob Agents Chemother. 2002 Jul;46(7):2284-6. PubMed PMID: 12069991; PubMed Central PMCID: PMC127290.

12: Kemper EM, Jansen B, Brouwer KR, Schellens JH, Beijnen JH, van Tellingen O. Bioanalysis and preliminary pharmacokinetics of the acridonecarboxamide derivative GF120918 in plasma of mice and humans by ion-pairing reversed-phase high-performance liquid chromatography with fluorescence detection. J Chromatogr B Biomed Sci Appl. 2001 Aug 5;759(1):135-43. PubMed PMID: 11499617.

13: Maliepaard M, van Gastelen MA, Tohgo A, Hausheer FH, van Waardenburg RC, de Jong LA, Pluim D, Beijnen JH, Schellens JH. Circumvention of breast cancer resistance protein (BCRP)-mediated resistance to camptothecins in vitro using non-substrate drugs or the BCRP inhibitor GF120918. Clin Cancer Res. 2001 Apr;7(4):935-41. PubMed PMID: 11309344.

14: Malingré MM, Beijnen JH, Rosing H, Koopman FJ, Jewell RC, Paul EM, Ten Bokkel Huinink WW, Schellens JH. Co-administration of GF120918 significantly increases the systemic exposure to oral paclitaxel in cancer patients. Br J Cancer. 2001 Jan 5;84(1):42-7. PubMed PMID: 11139311; PubMed Central PMCID: PMC2363627.

15: Bardelmeijer HA, Beijnen JH, Brouwer KR, Rosing H, Nooijen WJ, Schellens JH, van Tellingen O. Increased oral bioavailability of paclitaxel by GF120918 in mice through selective modulation of P-glycoprotein. Clin Cancer Res. 2000 Nov;6(11):4416-21. PubMed PMID: 11106262.

16: Evers R, Kool M, Smith AJ, van Deemter L, de Haas M, Borst P. Inhibitory effect of the reversal agents V-104, GF120918 and Pluronic L61 on MDR1 Pgp-, MRP1- and MRP2-mediated transport. Br J Cancer. 2000 Aug;83(3):366-74. PubMed PMID: 10917553; PubMed Central PMCID: PMC2374556.

17: de Bruin M, Miyake K, Litman T, Robey R, Bates SE. Reversal of resistance by GF120918 in cell lines expressing the ABC half-transporter, MXR. Cancer Lett. 1999 Nov 15;146(2):117-26. PubMed PMID: 10656616.

18: Traunecker HC, Stevens MC, Kerr DJ, Ferry DR. The acridonecarboxamide GF120918 potently reverses P-glycoprotein-mediated resistance in human sarcoma MES-Dx5 cells. Br J Cancer. 1999 Nov;81(6):942-51. PubMed PMID: 10576649; PubMed Central PMCID: PMC2362940.

19: Sparreboom A, Planting AS, Jewell RC, van der Burg ME, van der Gaast A, de Bruijn P, Loos WJ, Nooter K, Chandler LH, Paul EM, Wissel PS, Verweij J. Clinical pharmacokinetics of doxorubicin in combination with GF120918, a potent inhibitor of MDR1 P-glycoprotein. Anticancer Drugs. 1999 Sep;10(8):719-28. PubMed PMID: 10573204.

20: Myer MS, Joone G, Chasen MR, van Rensburg CE. The chemosensitizing potential of GF120918 is independent of the magnitude of P-glycoprotein-mediated resistance to conventional chemotherapeutic agents in a small cell lung cancer line. Oncol Rep. 1999 Jan-Feb;6(1):217-8. PubMed PMID: 9864431.

21: Van Rensburg CE, Jooné G, Anderson R. Alpha-tocopherol antagonizes the multidrug-resistance-reversal activity of cyclosporin A, verapamil, GF120918, clofazimine and B669. Cancer Lett. 1998 May 15;127(1-2):107-12. PubMed PMID: 9619865.

22: Letrent SP, Pollack GM, Brouwer KR, Brouwer KL. Effect of GF120918, a potent P-glycoprotein inhibitor, on morphine pharmacokinetics and pharmacodynamics in the rat. Pharm Res. 1998 Apr;15(4):599-605. PubMed PMID: 9587957.

23: Germann UA, Ford PJ, Shlyakhter D, Mason VS, Harding MW. Chemosensitization and drug accumulation effects of VX-710, verapamil, cyclosporin A, MS-209 and GF120918 in multidrug resistant HL60/ADR cells expressing the multidrug resistance-associated protein MRP. Anticancer Drugs. 1997 Feb;8(2):141-55. PubMed PMID: 9073310.

24: den Ouden D, van den Heuvel M, Schoester M, van Rens G, Sonneveld P. In vitro effect of GF120918, a novel reversal agent of multidrug resistance, on acute leukemia and multiple myeloma cells. Leukemia. 1996 Dec;10(12):1930-6. PubMed PMID: 8946933.

25: Hyafil F, Vergely C, Du Vignaud P, Grand-Perret T. In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative. Cancer Res. 1993 Oct 1;53(19):4595-602. PubMed PMID: 8402633.