Elacridar hydrochloride

Elacridar is an inhibitor of breast cancer resistance protein (BCRP) and P-glycoprotein (P-GP) that has been used to improve the brain distribution of drugs. Recent studies have revealed that elacridar could probably be the substrate of these multidrug transporters (MDTs) [2].
Recent studies had shown that elacridar and taxanes co-administrated orally could increase plasma concentrations of docetaxel (four-fold) and paclitaxel (10.7-fold) in mice. Co-administration of elacridar with taxanes and ritonavir could lead to a further increase in plasma concentrations of docetaxel (37.4-fold) and paclitaxel (31.9-fold). Besides, co-administration of elacridar with taxanes and ritonavir could potently increase taxanes concentration in the brain, but not increase the brain penetration of the taxanes [1].
Elacridar co-administrated orally with crizotinib has shown to increase the crizotinib concentrations in plasma and brain as well as increase the brain-to-plasma ratios of crizotinib, indicating that co-administration of crizotinib with elacridar could increase oral availability of crizotinib and delivery of crizotinib to the brain [2].
Apart from these, the uptake of elacridar at nanomolar doses in mouse brain was proved to be limited by Pgp- and Bcrp1-induced efflux at the blood - brain barrier. In vitro, Elacridar was indicated a low intracellular accumulation at nanomolar concentrations and a high intracellular accumulation at micromolar concentrations in Pgp- and Bcrp1-overexpressing cell lines [3].
References:
1.Hendrikx JJ1, Lagas JS2, Wagenaar E3, Rosing H2, Schellens JH4, Beijnen JH5, Schinkel AH3. Oral co-administration of elacridar and ritonavir enhances plasma levels of oral paclitaxel and docetaxel without affecting relative brain accumulation. Br J Cancer. 2014 May 27;110(11):2669-76. doi: 10.1038/bjc.2014.222. Epub 2014 Apr 29.
2.Chuan Tang S1, Nguyen LN, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH.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. doi: 10.1002/ijc.28475. Epub 2013 Oct 3.
3.Bankstahl JP1, Bankstahl M, Römermann K, Wanek T, Stanek J, Windhorst AD, Fedrowitz M, Erker T, Müller M, Löscher 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 positron emission tomography and in vitro study. Drug Metab Dispos. 2013 Apr;41(4):754-62. doi: 10.1124/dmd.112.049148. Epub 2013 Jan 10.

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.

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.[Pubmed:9864431]

Oncol Rep. 1999 Jan-Feb;6(1):217-8.

GF120918, at 250 ng/ml, increased the sensitivity of a P-glycoprotein (P-gp)-mediated multidrug resistant (MDR) small cell lung cancer cell line (H69/LX4) to the P-gp substrates, paclitaxel, taxotere, vinblastine, vinorelbine, daunorubicin and etoposide to levels which were either greater (in the case of etoposide) or close to that of the parent cell line (H69/P). This was achieved in spite of the great variation in the levels of resistance of the MDR cell line for the various anti-cancer drugs tested. These data suggest that GF120918 is a potent antagonist of P-gp mediated multidrug resistance, even in the case of high levels of resistance, as was the case with paclitaxel and taxotere (2560 and 2215 fold more than the sensitive parent cell line respectively).

In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative.[Pubmed:8402633]

Cancer Res. 1993 Oct 1;53(19):4595-602.

N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]- phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) has been selected from a chemical program aimed at identifying an optimized inhibitor of multidrug resistance (MDR). The potency of GF120918 is assessed by dose-dependent sensitization of CHRC5, OV1/DXR and MCF7/ADR cells to the cytotoxicity of doxorubicin and vincristine respectively: GF120918 fully reverses multidrug resistance at 0.05 to 0.1 microM and is half maximally active at 0.02 microM. The spectrum of drugs sensitized by GF120918 coincides with those having the classical MDR phenotype. In CHRC5 cells, 0.01-0.1 microM GF120918 enhances the uptake of [3H]daunorubicin and blocks the efflux from preloaded cells. It is also shown that GF120918 is still active several hours after being taken away from the culture medium showing that it is not, like verapamil, effluxed rapidly by P-glycoprotein. GF120918 effectively competes with [3H]azidopine for binding P-glycoprotein, pointing to this transport membrane protein as its likely site of action. After i.v. administration to mice, GF120918 penetrates thoroughly various organs that have a tissue level/blood level ratio above 10. It is eliminated from organs and blood with a half-time of approximately 2.7 h. It is well absorbed after p.o. administration. In mice implanted i.p. with the MDR P388/Dox tumor, a single i.v. or p.o. dose of GF120918 restores sensitivity of the tumor to a single i.p. dose (5 mg/kg) of doxorubicin administered 1 h later. A statistically significant effect is observed at 1 mg/kg GF120918 i.v. and maximal effect is reached at 5 mg/kg. Similarly, whereas neither drug alone is effective, GF120918 (10 mg/kg i.p.) associated with doxorubicin (5 mg/kg i.p.) inhibits the growth of the moderately MDR C26 tumor implanted s.c. as assessed by tumor size at day 19. GF120918 does not modify significantly the distribution or the elimination of doxorubicin in mice ruling out the possibility that the antitumor effects seen might be explained by pharmacokinetic interactions.

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.

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