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.

Figure 1. Plasma pharmacokinetic profile of NSC23925b after intraperitoneal injection/intravenous injection (I.P./I.V.) administration.

(A) Plasma concentration-time profile of NSC23925b in male BALB/c mice at 5.00 mg/kg (I.P.) alone, 2.50 mg/kg (I.V.) alone, and co-administered with paclitaxel/doxorubicin; (B) single-dose plasma pharmacokinetics of NSC23925b in male Sprague-Dawley rats following 5.00 mg/kg (I.P.) alone, 2.50 mg/kg (I.V.) alone, and co-administered with paclitaxel/doxorubicin. Data: mean ± SD of each time point.

Figure 2. Plasma pharmacokinetic profile of paclitaxel and doxorubicin after intravenous injection (I.V.) alone or co-administration with NSC23925b.

Plasma concentration-time course of paclitaxel in male BALB/c mice at a single 5.00 mg/kg dose (A), and in male Sprague-Dawley rats at a single 5.00 mg/kg dose (B); plasma concentration-time curves of doxorubicin in male BALB/c mice at a single 2.00 mg/kg dose (C), and in male Sprague-Dawley rats at a single 1.00 mg/kg dose (D). Data: mean ± SD of each time point.

Figure 3. Comparison of inhibitive potentials between NSC23925b and reference inhibitors on human cytochrome (CYP) 450s (CYP1A2, 2B6, 2C8, 2C19, 2D6, and 3A4).

The concentration-effect sigmoid-shaped plots of NSC23925b and particular reference inhibitor against the respective CYP450 enzyme, CYP1A2 (A), CYP2B6 (B), CYP2C8 (C), CYP2C19 (D), CYP2D6 (E), and CYP3A4 (F,G). The red triangles and line represent NSC23925b, and the black dots and line indicates the reference inhibitors. “NC” stands for normal control (saline).