Gao Yan, Shen Jacson K, Choy Edwin, Zhang Zhan, Mankin Henry J, Hornicek Francis J, Duan Zhenfeng
Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Department of Clinical Laboratory Diagnostics, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
Sci Rep. 2016 May 9;6:25659. doi: 10.1038/srep25659.
Overexpression of P-glycoprotein (Pgp) increases multidrug resistance (MDR) in cancer, which greatly impedes satisfactory clinical treatment and outcomes of cancer patients. Due to unknown pharmacokinetics, the use of Pgp inhibitors to overcome MDR in the clinical setting remains elusive despite promising in vitro results. The purpose of our current preclinical study is to investigate the pharmacokinetics and tolerability of NSC23925b, a novel and potent P-glycoprotein inhibitor, in rodents. Plasma pharmacokinetic studies of single-dose NSC23925b alone or in combination with paclitaxel or doxorubicin were conducted in male BALB/c mice and Sprague-Dawley rats. Additionally, inhibition of human cytochrome P450 (CYP450) by NSC23925b was examined in vitro. Finally, the maximum tolerated dose (MTD) of NSC23925b was determined. NSC23925b displayed favorable pharmacokinetic profiles after intraperitoneal/intravenous (I.P./I.V.) injection alone or combined with chemotherapeutic drugs. The plasma pharmacokinetic characteristics of the chemotherapy drugs were not affected when co-administered with NSC23925b. All the animals tolerated the I.P./I.V. administration of NSC23925b. Moreover, the enzymatic activity of human CYP450 was not inhibited by NSC23925b. Our results demonstrated that Pgp inhibitor NSC23925b exhibits encouraging preclinical pharmacokinetic characteristics and limited toxicity in vivo. NSC23925b has the potential to treat cancer patients with MDR in the future.
P-糖蛋白（Pgp）的过表达会增加癌症中的多药耐药性（MDR），这极大地阻碍了癌症患者获得满意的临床治疗和疗效。由于药代动力学尚不明确，尽管体外实验结果很有前景，但在临床环境中使用Pgp抑制剂来克服MDR仍然难以实现。我们当前临床前研究的目的是调查新型强效P-糖蛋白抑制剂NSC23925b在啮齿动物中的药代动力学和耐受性。在雄性BALB/c小鼠和Sprague-Dawley大鼠中进行了单剂量NSC23925b单独或与紫杉醇或阿霉素联合使用的血浆药代动力学研究。此外，还在体外检测了NSC23925b对人细胞色素P450（CYP450）的抑制作用。最后，确定了NSC23925b的最大耐受剂量（MTD）。单独腹腔内/静脉内（I.P./I.V.）注射或与化疗药物联合使用后，NSC23925b显示出良好的药代动力学特征。与NSC23925b共同给药时，化疗药物的血浆药代动力学特征未受影响。所有动物都耐受NSC23925b的I.P./I.V.给药。此外，NSC23925b未抑制人CYP450的酶活性。我们的结果表明，Pgp抑制剂NSC23925b在体内表现出令人鼓舞的临床前药代动力学特征和有限的毒性。NSC23925b未来有潜力治疗患有MDR的癌症患者。
