Multidrug resistance (MDR) is one of the major obstacles confronted in cancer chemotherapy; this obstacle is mainly due to the overexpression of P-glycoprotein (P-gp). Co-administration of anticancer drugs and P-gp inhibitors is a promising approach to overcome MDR. WYX-5, a novel P-gp inhibitor, shows a notable reversal effect with low cytotoxicity in vitro. In this paper, the reversal mechanism and safety of the MDR modulator WYX-5 were explored in vitro, and evaluated for its pharmacokinetics and effects on adriamycin (ADM) metabolism in vivo. The results suggest that WYX-5 is a potent P-gp inhibitor with EC50 in nanomole range (EC50 = 204.3 ± 20.2 nmol·L-1), relative safety (therapeutic index = 446.4), which performs as a substrate of P-gp and retrains its function. Further, WYX-5 (5 mg·kg-1) had relatively ideal pharmacokinetic properties (T1/2 = 6.448 h, F = 96.05%) without interactions with ADM metabolism in vivo. In conclusion, WYX-5 may be a promising candidate for MDR cancer combined-chemotherapy research.
Keywords: MDR; P-gp inhibitor; adriamycin; adriamycine; in vivo; inhibiteur de la P-gp; multidrug resistance; multirésistance aux médicaments; pharmacocinétique; pharmacokinetics; renversement; reversal.