title: Reversal of P-glycoprotein-medicated multidrug resistance by LBM-A5 in vitro and a study of its pharmacokinetics in vivo.
abstract: The overexpression of P-glycoprotein (P-gp) in tumors leads to multidrug resistance (MDR), which is a significant obstacle in clinical cancer chemotherapy. The co-administration of anticancer drugs and MDR modulators is a promising strategy for overcoming this problem. Our study aimed to explore the reversal mechanism and safety of the MDR modulator LBM-A5 in vitro, and evaluate its pharmacokinetics and effects on doxorubicin metabolism in vivo. We evaluated an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay of anticancer agents mediated by LBM-A5, the effect of LBM-A5 on rhodamine123 intracellular accumulation, and the efflux in K562/DOX cells to investigate the reversal mechanisms of LBM-A5. The results showed that LBM-A5 inhibits rhodamine123 efflux and increases intracellular accumulation by inhibiting the efflux pump function of P-gp. Furthermore, the therapeutic index and CYP3A4 activity analysis in vitro suggested that LBM-A5 is reasonably safe to use. Also, LBM-A5 (10 mg/kg body mass) achieved the required plasma concentration in sufficient time to reverse MDR in vivo. Importantly, the LBM-A5 treatment group shared similar doxorubicin (DOX) pharmacokinetics with the free DOX group. Our results suggest that LBM-A5 effectively reverses MDR (EC50 = 483.6 ± 81.7 nmol·L(-1)) by inhibiting the function of P-gp, with relatively ideal pharmacokinetics and in a safe manner, and so may be a promising candidate for cancer chemotherapy research.
authors.affiliation: a Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, Jiangsu 210009, China.
authors.forename: Tianxiao
authors.initials: T
authors.lastname: Zhao
authors.forename: Yun
authors.initials: Y
authors.lastname: Song
authors.forename: Baomin
authors.initials: B
authors.lastname: Liu
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Qiu
authors.forename: Lei
authors.initials: L
authors.lastname: Jiao
authors.forename: Yunman
authors.initials: Y
authors.lastname: Li
authors.forename: Wenlong
authors.initials: W
authors.lastname: Huang
authors.forename: Hai
authors.initials: H
authors.lastname: Qian
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D020014:K562 Cells; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents
keywords: P-glycoprotein inhibitor; inhibiteur de la P-glycoprotéine; modulateur; modulator; safety; sécurité