title: Pharmacokinetics and tolerability of NSC23925b, a novel P-glycoprotein inhibitor: preclinical study in mice and rats.
abstract: 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.
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Jacson K
authors.initials: JK
authors.lastname: Shen
authors.affiliation: Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: Choy
authors.affiliation: Shangqiu Medical College, Shangqiu 476100, Henan Province, China.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Mankin
authors.affiliation: Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Hornicek
authors.affiliation: Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Duan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007536:Isomerism; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008807:Mice, Inbred BALB C; D017239:Paclitaxel / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D011804:Quinolines / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D017207:Rats, Sprague-Dawley
chemical_list: C546115:(2-(4-methoxyphenyl)-4-quinolinyl)(2-piperidinyl)methanol; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D010880:Piperidines; D011804:Quinolines; D004317:Doxorubicin; D003577:Cytochrome P-450 Enzyme System; D017239:Paclitaxel