Effect of the ABCB1 modulators elacridar and tariquidar on the distribution of paclitaxel in nude mice

Abstract

Elacridar and tariquidar seem to modulate p-glycoprotein preferentially at the blood-brain barrier. Our results suggest that the systemic toxicity of cytostatics combined with elacridar or tariquidar should be lower than in combination with valspodar.

Pharmacokinetic Assessment of Efflux Transport in Sunitinib Distribution to the Brain

“…The influence of selective or dual pharmacological inhibition of P-gp and Bcrp on the brain distribution of sunitinib was examined by pretreating FVB wildtype mice with selective inhibitors of P-gp (zosuquidar, LY335979) (Shepard et al, 2003), Bcrp (Ko143) (Allen et al, 2002), and a dual inhibitor of P-gp/Bcrp (elacridar, GF120918) (Maliepaard et al, 2001;Hubensack et al, 2008). Zosuquidar was administered at a dose of 25 mg/kg, and both Ko143 and elacridar were administered at doses of 10 mg/kg (vehicle: 40% dimethylsulfoxide, 40% propylene glycol, 20% saline).…”

Drug Efflux Transporters and Multidrug Resistance in Acute Leukemia: Therapeutic Impact and Novel Approaches to Mediation

“…For example, zosuquidar restored drug sensitivity in P-gp-expressing leukemia cell lines and enhanced anthracycline cytotoxicity in P-gp-active primary AML blasts (Tang et al, 2008). Tariquidar was shown to be a highly effective P-gp inhibitor (Fox and Bates, 2007), increasing paclitaxel concentrations in the brain (Hubensack et al, 2008) and reversing MDR in both in vitro and in vivo studies (Mistry et al, 2001). Likewise, the imidazole derivative (E)-methyl-3-[4- [4,5-bis(4-[isopropyl(methyl)amino]phenyl)-1H-imidazol-2-yl]phenyl]acrylate (FG020326) potentiated paclitaxel, doxorubicin, and vincristine activity in P-gp-overexpressing cell lines and enhanced paclitaxel and vincristine antitumor activities in vivo (Dai et al, 2009).…”

Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non-small cell lung cancer

“…Inhibitors of ABCB1, which reverse the ABCB1 efflux pump, have been studied for more than twenty years, and third-generation drugs, such as elacridar (GF120918), have been developed (9,19). They specifically and potently inhibit ABCB1 and generally do not alter the plasma pharmacokinetics of simultaneously administered antitumor agents, and therefore show potential for combined application with anticancer drugs to combat chemotherapeutic resistance (19)(20)(21) Departments of 1 General Thoracic Surgery and Breast and Endocrinological Surgery, 2 Bioinformatics and Cellular phenotypes in addition to ABC molecules have been shown to be associated with multidrug resistance (22). Epithelial-mesenchymal transition (EMT) phenotype, loss of epithelial characteristics (E-cadherin), and acquisition of mesenchymal properties (vimentin, fibronectin, or N-cadherin), have been shown to play a crucial role in drug resistance of cancer cells against conventional therapeutics including taxane, vincristine, oxaliplatin, as well as epidermal growth factor receptor (EGFR)-targeted agents (23)(24)(25).…”