Kd: 5.1 nM (P-gp)

Tariquidar methanesulfonate, hydrate (XR9576 methanesulfonate, hydrate) is a potent modulator of P-gp mediated [ ³ H]-Vinblastine and [ ³ H]-Paclitaxel transport as it increases the steady-state accumulation of these cytotoxics in CH ^r B30 cells to levels observed in non-P-gp-expressing AuxB1 cells (EC ₅₀ =487±50 nM). [ ³ H]-Tariquidar binds to CH ^r B30 membranes with the highest affinity (K _d =5.1±0.9 nM, n=7) and a binding capacity (B _max ) of 275±15 pmol/mg membrane protein. In contrast to the parental cell line, the accumulation of [ ³ H]-Vinblastine is increased in a dose-dependent fashion by the modulators XR9576 (EC ₅₀ =487±50 nM). The MDR modulator Tariquidar is able to inhibit 60-70% of the vanadate-sensitive ATPase activity, with potent IC ₅₀ value of 43±9 nM. Tariquidar (XR9576) potentiates the cytotoxicity of several drugs including Doxorubicin, Paclitaxel, Etoposide, and Vincristine; complete reversal of resistance is achieved in the presence of 25-80 nM Tariquidar. Tariquidar is a potent inhibitor of photoaffinity labeling of P-gp by [ ³ H]Azidopine implying a direct interaction with the protein.

In mice bearing the intrinsically resistant MC26 colon tumors, coadministration of Tariquidar methanesulfonate, hydrate (XR9576 methanesulfonate, hydrate) potentiates the antitumor activity of Doxorubicin without a significant increase in toxicity; maximum potentiation is observed at 2.5-4.0 mg/kg dosed either i.v. or p.o. In addition, coadministration of Tariquidar (6-12 mg/kg p.o.) fully restores the antitumor activity of Paclitaxel, Etoposide, and Vincristine against two highly resistant MDR human tumor xenografts (2780AD, H69/LX4) in nude mice. Tariquidar is found to also significantly potentiate the antitumor activity of doxorubicin against s.c. MC26 tumors in vivo.