单位：[1]Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA[2]Department of Clinical Laboratory Diagnostics, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China医技科室检验科检验科首都医科大学附属北京友谊医院[3]Shangqiu Medical College, Shangqiu 476100, Henan Province, China
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.
基金：
Wechsler fund; Kenneth Stanton Fund; Sarcoma Foundation of America (SFA); National Cancer Institute (NCI)/National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [UO1]; Academic Enrichment Fund of MGH Orthopaedics; China Scholarship CouncilChina Scholarship Council; Excellent Doctoral Dissertations Grant of Zhengzhou University; Gattegno fund
第一作者单位：[1]Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA[2]Department of Clinical Laboratory Diagnostics, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
通讯作者：
推荐引用方式(GB/T 7714)：
YanGao,Jacson K. Shen,EdwinChoy,et al.Pharmacokinetics and tolerability of NSC23925b, a novel P-glycoprotein inhibitor: preclinical study in mice and rats[J].SCIENTIFIC REPORTS.2016,6:doi:10.1038/srep25659.
APA：
YanGao,Jacson K. Shen,EdwinChoy,ZhanZhang,Henry J. Mankin...&Zhenfeng Duan.(2016).Pharmacokinetics and tolerability of NSC23925b, a novel P-glycoprotein inhibitor: preclinical study in mice and rats.SCIENTIFIC REPORTS,6,
MLA：
YanGao,et al."Pharmacokinetics and tolerability of NSC23925b, a novel P-glycoprotein inhibitor: preclinical study in mice and rats".SCIENTIFIC REPORTS 6.(2016)
