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.

Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation

“…After a single subcutaneous (S.C.) administration of aptscl56 or Apc001PE in rats, blood samples (~200 μl) were collected at different time points (aptscl56: 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h; Apc001PE: 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, 30 h, 36 h, 48 h, 54 h, 62 h, 70 h, 76 h, 84 h, 96 h, 107 h, n = 6 in each group) via the orbital vein 51 , 52 . The plasma was isolated within 1 h and stored at −80 °C 51 , 53 , 54 . Prior to analysis, plasma samples were incubated with proteinase K solution (1 mg/ml proteinase K in 10 mM Tris HCl, pH 7.5, 20 mM CaCl 2 , 10% glycerol v/v) in digestion buffer (60 mM Tris-HCl, pH 8.0, 100 mM EDTA and 0.5% SDS) at 55 °C overnight with shaking.…”

“…The column oven temperature was 50 °C. Standards were prepared in blank rat plasma containing sodium heparin with different concentrations of aptscl56/Apc001PE 53 . All reported concentrations of aptscl56 and Apc001PE were based on the mass of aptscl56.…”

1,8 Cineole and Ellagic acid inhibit hepatocarcinogenesis via upregulation of MiR-122 and suppression of TGF-β1, FSCN1, Vimentin, VEGF, and MMP-9

“…[ 24 ] or with a weekly injection of doxorubicin hydrochloride (2 mg/kg i.p.) [ 25 ], respectively for the last four weeks after HCC induction . Group 6 and 7 (EA/Dox and Cin/Dox) were DEN/2-AAF induced HCC rats administered in combination with the same doses as each alone.…”

Model-based analysis of treatment effects of paclitaxel microspheres in a microscopic peritoneal carcinomatosis model in mice

“…PTX-ethanolic loaded GP-MS (PTX EtOH -GP-MS): GP-MS were loaded with PTX by immersion in an ethanolic PTX solution. 200 mg GP-MS with different degrees of crosslinking (7,25,40, 60 and 70%) were immersed in 2 ml of a 1, 2.5 or 5 mg/ml PTX (purity of >99%, LC laboratories, Woburn, MA, USA) ethanol/distilled water (75/25, v/v) (absolute ethanol, VWR chemicals, Fontenay-sous-Bois cedex, France) solution under slow magnetic stirring. After 3 hours, GP-MS were vacuum filtered and washed with absolute ethanol (VWR chemicals) to remove unentrapped PTX from the surface.…”