Reversal of P-glycoprotein-mediated multidrug resistance and pharmacokinetics study in rats by WYX-5.
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 EC50in 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.
a Center for Drug Evaluation, CFDA, Beijing, PR China.|b Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, PR China.
Yuzhu
Y
Wang
b Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, PR China.
Jian
J
Cui
b Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, PR China.
Yuxuan
Y
Dai
b Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, PR China.
Yuxiang
Y
Wu
b Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, PR China.|c Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing, PR China.
Wenlong
W
Huang
b Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, PR China.|c Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing, PR China.
Hai
H
Qian
d School of Pharmacy, China Pharmaceutical University, Nanjing, PR China.
Liang
L
Ge
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D004347:Drug Interactions; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006801:Humans; D007546:Isoquinolines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D020014:K562 Cells; D008297:Male; D051381:Rats; D014230:Triazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D007546:Isoquinolines; D014230:Triazoles; C000625675:WYX-5 compound; D004317:Doxorubicin
MDR; P-gp inhibitor; adriamycin; adriamycine; in vivo; inhibiteur de la P-gp; multidrug resistance; multirésistance aux médicaments; pharmacocinétique; pharmacokinetics; renversement; reversal