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 Tariquidar

Description of Tariquidar: Tariquidar is a P-glycoprotein inhibitor undergoing research as an adjuvant against multidrug resistance in cancer. Tariquidar non-competitively binds to the p-glycoprotein transporter, thereby inhibiting transmembrane transport of anticancer drugs. Inhibition of transmembrane transport may result in increased intracellular concentrations of an anticancer drug, thereby augmenting its cytotoxicity. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

According to news published on 19 May 2003,  QLT has discontinued its Phase III trials of tariquidar, licensed from the UK's Xenova, as an adjunctive treatment for patients with non-small cell lung cancer. Tariquidar had been tipped for a launch in 2005, providing all went well with the pivotal trials program, and at one time was forecast to achieve annual sales of $500 million or more at its peak.

Current developer:  QLT Inc. and Xenova.

P-glycoprotein actively transports structurally unrelated compounds out of cells, conferring the multidrug resistance phenotype in cancer. Tariquidar is a potent, specific, noncompetitive inhibitor of P-glycoprotein. Tariquidar inhibits the ATPase activity of P-glycoprotein, suggesting that the modulating effect is derived from the inhibition of substrate binding, inhibition of ATP hydrolysis or both. In clinical trials, tariquidar is tolerable and does not have significant pharmacokinetic interaction with chemotherapy. In patients, inhibition of P-glycoprotein has been demonstrated for 48 h after a single dose of tariquidar. Studies to assess a possible increase in toxicity of chemotherapy and the impact of P-glycoprotein inhibition on tumor response and patient outcome are ongoing. Tariquidar can be considered an ideal agent for testing the role of P-glycoprotein inhibition in cancer. (source:  Expert Rev Anticancer Ther. 2007 Apr;7(4):447-59.)

Highlight on recent research using Tariquidar:

Docetaxel  plus Tariquidar in Patients with Lung, Ovarian, and Cervical Cancer:  Forty-eight patients were enrolled onto the trial. Nonhematologic grade 3/4 toxicities in 235 cycles were minimal. Tariquidar inhibited Pgp-mediated rhodamine efflux from CD56(+) cells and reduced (99m)Tc-sestamibi clearance from the liver. There was striking variability in basal sestamibi uptake; a 12% to 24% increase in visible lesions was noted in 8 of 10 patients with lung cancer. No significant difference in docetaxel disposition was observed in pairwise comparison with and without tariquidar. Four partial responses (PR) were seen (4/48); 3 in the non-small cell lung cancer (NSCLC) cohort, measuring 40%, 57%, and 67% by RECIST, and 1 PR in a patient with ovarian cancer. CONCLUSIONS: Tariquidar is well tolerated, with less observed systemic pharmacokinetic interaction than previous Pgp antagonists. Variable effects of tariquidar on retention of sestamibi in imageable lung cancers suggest that follow-up studies assessing tumor drug uptake in this patient population would be worthwhile. (see: Clin Cancer Res. 2011 Feb 1;17(3):569-580.)

Tariquidar is a substrate and an inhibitor for breast cancer resistance protein (BCRP/ABCG2). Tariquidar was developed as a specific inhibitor of the efflux transporter ABCB1. Recent positron emission tomographic brain imaging studies using [11C]tariquidar to measure ABCB1 (P-gp, P-glycoprotein) density in mice indicate that the inhibitor may not be as specific as previously thought. We examined its selectivity as an inhibitor and a substrate for the human transporters P-gp, breast cancer resistance protein (BCRP, ABCG2), and multidrug resistance protein 1 (MRP1, ABCC1). Our results show that at low concentrations, tariquidar acts selectively as an inhibitor of P-gp and also as a substrate of BCRP. At much higher concentrations (≥100 nM), tariquidar acts as an inhibitor of both P-gp and BCRP. Thus, the in vivo specificity of tariquidar depends on concentration and the relative density and capacity of P-gp vs BCRP. [source:  ACS Chem. Neurosci., 2011, 2 (2), pp 82–89]

Tariquidar may overcome bacterial multidrug resistance by increasing intracellular drug concentration. Activity of tariquidar and elacridar was comparable for S. aureus strains, and both dose-dependently increased susceptibility towards ciprofloxacin. Highest effects were observed for SA1199B, where the addition of tariquidar resulted in a 10-fold reduction of the ciprofloxacin MIC, while no effect was observed for P. aeruginosa. For S. maltophilia, elacridar but not tariquidar improved susceptibility. Uptake of [(14)C]ciprofloxacin and modification of susceptibility showed significant correlations (r = 0.89, P < 0.0001). Tariquidar had no intrinsic activity against any strain tested. Conclusions: We conclude that tariquidar has potent inhibitory effect against certain bacterial efflux pumps in vitro. Their high activity at clinically achievable concentrations might yield this class of drugs promising for future applications in infectious disease [source:  J Antimicrob Chemother. 2011, 66(4):834-9.]

Publications related to Tariquidar:

1: Bauer M, Zeitlinger M, Karch R, Matzneller P, Stanek J, Jäger W, Böhmdorfer M, Wadsak W, Mitterhauser M, Bankstahl JP, Löscher W, Koepp M, Kuntner C, Müller M, Langer O. Pgp-Mediated Interaction Between (R)-[(11)C]Verapamil and Tariquidar at the Human Blood-Brain Barrier: A Comparison With Rat Data. Clin Pharmacol Ther. 2011 Dec 14. doi: 10.1038/clpt.2011.217. [Epub ahead of print] PubMed PMID: 22166851.

2: 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 [(11)C]tariquidar, [ (11)C]elacridar and (R)-[ (11)C]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.

3: Patel NR, Rathi A, Mongayt D, Torchilin VP. Reversal of multidrug resistance by co-delivery of tariquidar (XR9576) and paclitaxel using long-circulating liposomes. Int J Pharm. 2011 Sep 15;416(1):296-9. Epub 2011 Jun 15. PubMed PMID: 21703341; PubMed Central PMCID: PMC3156341.

4: Puentes CO, Höcherl P, Kühnle M, Bauer S, Bürger K, Bernhardt G, Buschauer A, König B. Solid phase synthesis of tariquidar-related modulators of ABC transporters preferring breast cancer resistance protein (ABCG2). Bioorg Med Chem Lett. 2011 Jun 15;21(12):3654-7. Epub 2011 Apr 28. PubMed PMID: 21570282.

5: Leitner I, Nemeth J, Feurstein T, Abrahim A, Matzneller P, Lagler H, Erker T, Langer O, Zeitlinger M. The third-generation P-glycoprotein inhibitor tariquidar may overcome bacterial multidrug resistance by increasing intracellular drug concentration. J Antimicrob Chemother. 2011 Apr;66(4):834-9. Epub 2011 Jan 19. PubMed PMID: 21393173.

6: Kelly RJ, Draper D, Chen CC, Robey RW, Figg WD, Piekarz RL, Chen X, Gardner ER, Balis FM, Venkatesan AM, Steinberg SM, Fojo T, Bates SE. A pharmacodynamic study of docetaxel in combination with the P-glycoprotein antagonist tariquidar (XR9576) in patients with lung, ovarian, and cervical cancer. Clin Cancer Res. 2011 Feb 1;17(3):569-80. Epub 2010 Nov 16. PubMed PMID: 21081657; PubMed Central PMCID: PMC3071989.

7: Bauer F, Kuntner C, Bankstahl JP, Wanek T, Bankstahl M, Stanek J, Mairinger S, Dörner B, Löscher W, Müller M, Erker T, Langer O. Synthesis and in vivo evaluation of [11C]tariquidar, a positron emission tomography radiotracer based on a third-generation P-glycoprotein inhibitor. Bioorg Med Chem. 2010 Aug 1;18(15):5489-97. Epub 2010 Jun 22. PubMed PMID: 20621487.

8: Wang M, Zheng DX, Luo MB, Gao M, Miller KD, Hutchins GD, Zheng QH. Synthesis of carbon-11-labeled tariquidar derivatives as new PET agents for imaging of breast cancer resistance protein (ABCG2). Appl Radiat Isot. 2010 Jun;68(6):1098-103. Epub 2010 Feb 13. PubMed PMID: 20181488.

9: 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.

10: Bauer M, Karch R, Neumann F, Wagner CC, Kletter K, Müller M, Löscher W, Zeitlinger M, Langer O. Assessment of regional differences in tariquidar-induced P-glycoprotein modulation at the human blood-brain barrier. J Cereb Blood Flow Metab. 2010 Mar;30(3):510-5. Epub 2009 Dec 16. PubMed PMID: 20010957; PubMed Central PMCID: PMC2949150.

11: Wagner CC, Bauer M, Karch R, Feurstein T, Kopp S, Chiba P, Kletter K, Löscher W, Müller M, Zeitlinger M, Langer O. A pilot study to assess the efficacy of tariquidar to inhibit P-glycoprotein at the human blood-brain barrier with (R)-11C-verapamil and PET. J Nucl Med. 2009 Dec;50(12):1954-61. Epub 2009 Nov 12. PubMed PMID: 19910428.

12: la Fougère C, Böning G, Bartmann H, Wängler B, Nowak S, Just T, Wagner E, Winter P, Rominger A, Förster S, Gildehaus FJ, Rosa-Neto P, Minuzzi L, Bartenstein P, Potschka H, Cumming P. Uptake and binding of the serotonin 5-HT1A antagonist [18F]-MPPF in brain of rats: effects of the novel P-glycoprotein inhibitor tariquidar. Neuroimage. 2010 Jan 15;49(2):1406-15. Epub 2009 Sep 28. PubMed PMID: 19796699.

13: Gardner ER, Smith NF, Figg WD, Sparreboom A. Influence of the dual ABCB1 and ABCG2 inhibitor tariquidar on the disposition of oral imatinib in mice. J Exp Clin Cancer Res. 2009 Jul 10;28:99. PubMed PMID: 19591692; PubMed Central PMCID: PMC2717937.

14: Pajeva IK, Wiese M. Structure-activity relationships of tariquidar analogs as multidrug resistance modulators. AAPS J. 2009 Sep;11(3):435-44. Epub 2009 Jun 6. Review. PubMed PMID: 19504188; PubMed Central PMCID: PMC2758111.

15: Abraham J, Edgerly M, Wilson R, Chen C, Rutt A, Bakke S, Robey R, Dwyer A, Goldspiel B, Balis F, Van Tellingen O, Bates SE, Fojo T. A phase I study of the P-glycoprotein antagonist tariquidar in combination with vinorelbine. Clin Cancer Res. 2009 May 15;15(10):3574-82. Epub 2009 May 5. PubMed PMID: 19417029.

16: Patil Y, Sadhukha T, Ma L, Panyam J. Nanoparticle-mediated simultaneous and targeted delivery of paclitaxel and tariquidar overcomes tumor drug resistance. J Control Release. 2009 May 21;136(1):21-9. Epub 2009 Feb 5. PubMed PMID: 19331851.

17: Kühnle M, Egger M, Müller C, Mahringer A, Bernhardt G, Fricker G, König B, Buschauer A. Potent and selective inhibitors of breast cancer resistance protein (ABCG2) derived from the p-glycoprotein (ABCB1) modulator tariquidar. J Med Chem. 2009 Feb 26;52(4):1190-7. PubMed PMID: 19170519.

18: Kurnik D, Sofowora GG, Donahue JP, Nair UB, Wilkinson GR, Wood AJ, Muszkat M. Tariquidar, a selective P-glycoprotein inhibitor, does not potentiate loperamide's opioid brain effects in humans despite full inhibition of lymphocyte P-glycoprotein. Anesthesiology. 2008 Dec;109(6):1092-9. PubMed PMID: 19034106.

19: Bankstahl JP, Kuntner C, Abrahim A, Karch R, Stanek J, Wanek T, Wadsak W, Kletter K, Müller M, Löscher W, Langer O. Tariquidar-induced P-glycoprotein inhibition at the rat blood-brain barrier studied with (R)-11C-verapamil and PET. J Nucl Med. 2008 Aug;49(8):1328-35. Epub 2008 Jul 16. PubMed PMID: 18632828.

20: 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.

21: Thoeringer CK, Wultsch T, Shahbazian A, Painsipp E, Holzer P. Multidrug-resistance gene 1-type p-glycoprotein (MDR1 p-gp) inhibition by tariquidar impacts on neuroendocrine and behavioral processing of stress. Psychoneuroendocrinology. 2007 Sep-Nov;32(8-10):1028-40. Epub 2007 Sep 19. PubMed PMID: 17881135.

22: Fox E, Bates SE. Tariquidar (XR9576): a P-glycoprotein drug efflux pump inhibitor. Expert Rev Anticancer Ther. 2007 Apr;7(4):447-59. Review. PubMed PMID: 17428165.

23: Globisch C, Pajeva IK, Wiese M. Structure-activity relationships of a series of tariquidar analogs as multidrug resistance modulators. Bioorg Med Chem. 2006 Mar 1;14(5):1588-98. Epub 2005 Nov 22. PubMed PMID: 16307883.

24: Pusztai L, Wagner P, Ibrahim N, Rivera E, Theriault R, Booser D, Symmans FW, Wong F, Blumenschein G, Fleming DR, Rouzier R, Boniface G, Hortobagyi GN. Phase II study of tariquidar, a selective P-glycoprotein inhibitor, in patients with chemotherapy-resistant, advanced breast carcinoma. Cancer. 2005 Aug 15;104(4):682-91. PubMed PMID: 15986399.

25: Di Nicolantonio F, Knight LA, Glaysher S, Whitehouse PA, Mercer SJ, Sharma S, Mills L, Prin A, Johnson P, Charlton PA, Norris D, Cree IA. Ex vivo reversal of chemoresistance by tariquidar (XR9576). Anticancer Drugs. 2004 Oct;15(9):861-9. PubMed PMID: 15457126.

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