Inhibitory effect of Schisandrin on the pharmacokinetics of poziotinib in vivo and in vitro by UPLC-MS/MS

Abstract

Background: As a pan-HER tyrosine kinase inhibitor with a promising application prospect, poziotinib is likely to be coadministered with Schisandrins in clinical treatment due to its anticancer activities.

Methods: Eighteen Sprague-Dawley rats were randomly divided into three groups: Schisandrin A group and Schisandrin B group (20 mg/kg daily for 1 week), and control group (vehicle). On day 8, poziotinib (2 mg/kg) was administered by oral gavage 30 min later. An in vitro study was developed to identify the possible mechanisms of Schisandrins on poziotinib metabolism. All analytes were detected by UPLC/MS-MS, and molecular docking was performed by AutoDock Tools.

Results: When rats were preadministered with Schisandrin A, AUC_(0-∞) and Cmax of poziotinib were obviously increased by 0.79- and 1.17-fold, whereas the Vz/F and CLz/F values were dramatically decreased. The results in Schisandrin B group presented similarly. Both Schisandrin A and Schisandrin B were mixed inhibitors of poziotinib in RLMs, and Schisandrin B showed stronger inhibitory activity with IC₅₀ values of 2.55 μM for M1 and 6.97 μM for M2. Molecular docking analysis demonstrated that Schisandrin A and Schisandrin B exhibited a strong binding ability towards CYP2D6 as compared to CYP3A4.

Conclusion: All results provided the direct evidence of the pharmacokinetic drug-drug interactions (DDIs) between Schisandrin and poziotinib. Thus, particular attention should be paid when poziotinib is taken together with Schisandrins in clinical practice.

Keywords: drug-drug interactions; molecular docking; pharmacokinetic; poziotinib; schisandrin.

FIGURE 1

Representative chromatogram of plasma sample at 1 h after oral administration of poziotinib in rats.

FIGURE 2

The mean plasma concentration‐time curves of poziotinib in control group, Schisandrin A group, and Schisandrin B group (n = 6).

FIGURE 3

Typical UPLC‐MS/MS chromatogram of rat liver microsomes (RLMs) after the incubation with poziotinib.

FIGURE 4

The half‐maximal inhibitory concentration (IC₅₀) curves of Schisandrin A (a, b) and Schisandrin B (c, d). Data are means ± SD (n = 3).

FIGURE 5

Lineweaver‐Burk plot and the secondary plots for Ki and αKi in the inhibition of poziotinib to M1 (a–c) and M2 (d–f) by various concentrations of Schisandrin A (0–60 μM for M1, and 0–30 μM for M2, respectively) in RLMs. Data are presented as means ± SD (n = 3).

FIGURE 6

Lineweaver‐Burk plot and the secondary plots for Ki and αKi in the inhibition of poziotinib to M1 (a–c) and M2 (d–f) by various concentrations of Schisandrin B (0–6 μM for M1, and 0–12 μM for M2, respectively) in RLMs. Data are presented as means ± SD (n = 3).

FIGURE 7

Molecular docking analysis of the interactions between the small molecules and target proteins. Interaction sites of CYP3A4 enzyme with Schisandrin A and poziotinib (a, b). Interaction sites of CYP3A4 enzyme with Schisandrin B and poziotinib (c, d). Interaction sites of CYP2D6 enzyme with Schisandrin A and poziotinib (e, f). Interaction sites of CYP2D6 enzyme with Schisandrin B and poziotinib (g, h). The yellow dotted lines represent hydrogen bonding interactions between CYP450 enzymes and poziotinib.