Disease relevance of Tariquidar

• There was one patient who experienced severe doxorubicin/docetaxel-related toxicity after tariquidar was added to her chemotherapy regimen [1].

High impact information on Tariquidar

• In 4-day cytotoxicity assays, ABCG2-mediated resistance to SN-38 and topotecan was abrogated in ABCG2-transfected HEK-293 cells treated with 1 micro M tariquidar, and ABCG2-transfected cells were 6-7-fold resistant to UCN-01 [2].
• We found that 100 micro M of the cyclin-dependent kinase inhibitor UCN-01 or 1 micro M of the P-glycoprotein inhibitor tariquidar inhibited ABCG2-mediated PhA transport [2].
• Furthermore, i.v. coadministration of XR9576 did not alter the plasma pharmacokinetics of paclitaxel [3].
• The in vitro activity of XR9576 was evaluated using a panel of human (H69/LX4, 2780AD) and murine (EMT6 AR1.0, MC26) MDR cell lines [3].
• The insensitivity of cultured normal cells may be explained, in part, by expression of the drug efflux pump P-glycoprotein, because addition of the P-glycoprotein inhibitor XR9576 (tariquidar) with FK228 resulted in increased histone acetylation and CAR expression [4].

Biological context of Tariquidar

• No significant difference was found in the metabolite-corrected plasma AUC (normalized to the injected dose) between the baseline and XR9576 modulator studies (P = 0.69) [5].
• We obtained biodistribution and radiation dose estimates for (18)F-paclitaxel (FPAC) in monkeys and studied the effects of a Pgp blocker (XR9576, tariquidar) on FPAC kinetics [5].
• In this article, we examine the electrical properties of the human leukemic cells (K562) and its MDR counterpart (K562AR) using dielectrophoresis and flow cytometry (with a membrane potential sensitive dye, DIOC5), both before and after treatment with XR9576 (a P-glycoprotein-specific MDR-reversal agent) [6].
• The apparent inhibition constant, Kapp, for the blockade of P-glycoprotein (P-gp) by four drugs, verapamil, cyclosporin A, XR9576 (tariquidar), and vinblastine, was measured by studying their ability to inhibit daunorubicin and calcein-AM efflux from four strains of Ehrlich cells with different levels of drug resistance and P-gp content [7].
• Structure-activity relationships of a series of tariquidar analogs as multidrug resistance modulators [8].

Anatomical context of Tariquidar

• Phase I trial of XR9576 in healthy volunteers demonstrates modulation of P-glycoprotein in CD56+ lymphocytes after oral and intravenous administration [9].
• However, with tariquidar, the loperamide dose-response curves for testes/plasma and brain/plasma concentration ratios were shifted 6- (p = 0.07) and 25-fold (p < 0.01) to the right, respectively (ED50 = 1.48 and 5.65 mg/kg), compared with the rhodamine 123 efflux curve (ED50 0.25 mg/kg) [10].
• METHODS: The effects of PHT on spontaneous seizure activity were investigated in the electrical post-status epilepticus rat model for temporal lobe epilepsy, before and after administration of tariquidar (TQD), a selective inhibitor of P-gp [11].
• Tariquidar is a novel inhibitor of P-gp that has been shown to reverse resistance to cytotoxic drugs in tumor cell lines and mouse xenografts [12].

Associations of Tariquidar with other chemical compounds

• Moreover, the highly potent P-gp inhibitor, the anthranilic acid derivative, XR9576, was able to restore the cytotoxic efficacy of both drugs in tumour spheroids comprising NCI/ADR(Res) cells [13].
• Validation included confirmation with known ABCG2 inhibitors: FTC, novobiocin, tariquidar, and quercetin [14].
• The secondary objectives were to evaluate P-gp expression by immunohistochemistry (IHC), to determine functional activity of the P-gp transporter before and after administration of tariquidar with serial technetium-99m ((99m)Tc)-sestamibi scans, and to correlate those parameters with clinical response [1].
• Third-generation drugs, which are highly specific for Pgp and which seem to have only modest effects on drug clearance, include tariquidar, zosuquidar, laniquidar, and ONT-093 [15].
• Using the Pgp substrate Tc-99m Sestamibi as an imaging agent, increased uptake has been seen in normal liver and kidney after administration of PSC 833, VX710 and XR9576 [16].
• Tariquidar had no effects on vinorelbine pharmacokinetics [17].
• No significant difference in docetaxel disposition was observed in pairwise comparison with and without tariquidar [18].

Gene context of Tariquidar

• Despite at least 10 attempts, resistance did not develop in the presence of the multidrug resistance (MDR) modulators PSC833, VX710, and XR9576 [19].
• Hence, XR9576 holds great promise for the treatment of P-gp-mediated MDR cancers [3].

Analytical, diagnostic and therapeutic context of Tariquidar

• In conclusion, XR9576 has demonstrated sustained inhibition of P-gp after i.v. and oral administration and, supported by the elimination half-life of about 24 h, XR9576 is being taken into Phase II as a once-daily agent [9].
• METHODS: Paired baseline and Pgp modulation (2 mg/kg XR9576) 4-h whole-body dynamic PET scans were obtained in 3 rhesus monkeys after injection of FPAC [5].
• During the study, the same chemotherapy was continued without dose modifications, but tariquidar (150 mg intravenously) was added to the treatment regimen [1].
• These data support the introduction of tariquidar in combination with chemotherapy to clinical trials of patients expressing P-gp [12].

References