生物活性

• 靶点	P-gp Kd:5.1nM

• 描述The multidrug resistance is an obstacle in the chemotherapy treatment (such as doxorubicin, vincristine, paclitaxel, TKIs) for many solid and haematological tumours. Many factors can cause the multidrug resistance. Among them, the overexpression of P-gp (ABCB1), of which vinblastine and paclitaxel is the substrate, on the surface of resistant cells is considered as a key factor mediating multidrug resistance. Thus, the increased bioavailable and brain accumulation of anticancer drugs can be achieved partially through inhibition of P-gp. Tariquidar is a potent P-gp transport modulator with IC50 value of 0.4μM, displaying specific high-affinity binding to P-gp with Kd of 5.1nM. The cellular study showed that the accumulation of vinblastine and paclitaxel can be increased in a dose-dependent manner by tariquidar with EC50 value of 487nM and 25.4nM, respectively, in CH^rB30 cells, not mediated through competition for transport^[1]. Co-administration of paclitaxel with tariquidar (p.o., 50mg/kg) led to a comparable increase and a long lasting 5-fold increase in the concentration of paclitaxel accumulation in the cytostatic in the brain of nude mice^[2].
• 作用机制Tariquidar can bind at a site which is distinct from the site of interaction of transport substrates and alter P-gp-mediated transport by affecting its rate of ATP hydrolysis.^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  A2780 cells	-	Function assay	30 mins	Inhibition of human Pgp in A2780 cells after 30 mins by Hoechst 33342 assay, IC50=0.12589 μM	18083034
  EMT6/AR1.0 cells	-	Function assay	1 h	Inhibition of mouse Pgp in EMT6/AR1.0 cells after 1 hr by daunorubicin accumulation assay, IC50=0.064 μM	18083034
  human CCD-18Co cells	-	Cytotoxic assay	48 h	Cytotoxicity against human CCD-18Co cells assessed as cell viability after 48 hrs by MTT assay, IC50=25 μM	26197160

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• 动物研究
  剂量	Rat[3] (i.v.): 1 mg/kg - 15 mg/kg; Mice[4] (i.p.): 6.5 mg/kg - 13 mg/kg; Mice[5] (p.o.): 6 mg/kg - 12 mg/kg
  给药途径	i.v., i.p., p.o.
  动物药代数据	Animal Rats[6] Dose 15 mg/kg Administration i.v. p.o. i.p. F 71.6% (p.o.) 91.4% (i.p.) AUC0→24h 25.2 μg·h/ml (i.v.) 18.1 μg·h/ml (p.o.) 23.8 μg·h/ml (i.p.) Tmax 0.5 μg/ml (i.v.) 4.0 μg/ml (p.o.) 2.0 μg/ml (i.p.) Cmax 1.9 μg/ml (i.v.) 1.2 μg/ml (p.o.) 1.5 μg/ml (i.p.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01663545	-	-	Completed	-	United States, Maryland ... more >> National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland, United States, 20892 Collapse <<
  NCT01547754	-	-	Terminated	-	United States, Maryland ... more >> National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland, United States, 20892 Collapse <<
  NCT01386476	-	-	Completed	-	United States, Maryland ... more >> National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland, United States, 20892 Collapse <<

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• 参考文献

• [1] Hubensack M, M¨¹ller C, et al. 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.

  [2] Martin C, Berridge G, et al. The molecular interaction of the high affinity reversal agent XR9576 with P-glycoprotein. Br J Pharmacol. 1999 Sep;128(2):403-11

  [3] Bankstahl JP, Kuntner C, et al. 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.

  [4] Foran E, Kwon DY, et al. CNS uptake of bortezomib is enhanced by P-glycoprotein inhibition: implications for spinal muscular atrophy. Neurobiol Dis. 2016 Apr;88:118-24.

  [5] Mistry P, Stewart AJ, et al. In vitro and in vivo reversal of P-glycoprotein-mediated multidrug resistance by a novel potent modulator, XR9576. Cancer Res. 2001 Jan 15;61(2):749-58.

  [6] Matzneller P, Kussmann M, et al. Pharmacokinetics of the P-gp Inhibitor Tariquidar in Rats After Intravenous, Oral, and Intraperitoneal Administration. Eur J Drug Metab Pharmacokinet. 2018 Oct;43(5):599-606.

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