Tariquidar is a highly selective, potent non-competitive inhibitor of P-glycoprotein. P-glycoprotein actively transports structurally unrelated compounds out of cells, conferring the multidrug resistance phenotype in cancer. P-gp is also expressed in normal tissues like blood brain barrier, gastrointestinal track, liver, spleen and kidney. Tariquidar profoundly inhibited P-glycoprotein in lymphocytes by 93.7% (95% confidence interval, 92.0-95.3%). Tariquidar (XR9576) inhibits the ATPase activity of P-glycoprotein, suggesting that the modulating effect is derived from both inhibition of substrate binding and inhibition of ATP hydrolysis or each of them.
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Source | J Biol Chem (2015). Figure 3. Tariquidar |
| Method | Disulfide Cross-linking Analysis | |
| Cell Lines | HEK 293 cells | |
| Concentrations | 0.5 μM | |
| Incubation Time | 16 h | |
| Results | Accordingly, we screened the rescue of 223 G251V processing mutants in which each position in the TM segment was replaced with arginine. HEK293 cells were transfected with each mutant and expressed for 16 h in the absence or presence of 0.5 μM tariquidar. |
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Source | J Biol Chem (2015). Figure 2. Tariquidar |
| Method | Expression and Maturation of G251V Arginine Mutants | |
| Cell Lines | HEK 293 cells | |
| Concentrations | 500, 1000 nM | |
| Incubation Time | 16 h | |
| Results | By contrast, a higher concentration (1000 nM) of tariquidar did not significantly inhibit cross-linking of the ICL (L175C(ICL1)/N820C(ICL3), A259C(ICL2)/W803C(ICL3), A266C(ICL2/F1086C(NBD2)) (Fig. 2B) or the NBD (C431(NBD1)/L1176C(NBD2), L531C(NBD1)/C1074(NBD2), and P517C(NBD1)/I1050C(NBD2)) mutants (Fig. 2C). |
| Cell Experiment | |
|---|---|
| Cell lines | HEK 293 cells |
| Preparation method | A sample of the isolated histidine-tagged P-gp was mixed with an equal volume of 10 mg/ml of sheep brain phosphatidylethanolamine that had been washed and suspended in TBS. ATPase activity was measured in the presence of various concentrations of tariquidar. |
| Concentrations | 0.25 µM, 0.5 µM, 1 µM, |
| Incubation time | 24 h |
| Animal Experiment | |
|---|---|
| Animal models | Balb/C mice |
| Formulation | water with 5% glucose |
| Dosages | 10 mg/kg |
| Administration | oral gavage |
| Molecular Weight | 646.73 |
| Formula | C38H38N4O6 |
| CAS Number | 206873-63-4 |
| Solubility (25°C) | DMSO 100 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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P-gb-IN-1 inhibitor. |
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