Pharmacokinetic interaction between a Chinese herbal formula Huosu Yangwei oral liquid and apatinib in vitro and in vivo

Abstract

Objectives This study aimed to evaluate the inhibitory effects of Huosu Yangwei oral liquid (HSYW) on cytochrome P450 enzymes (CYPs) and to investigate whether this herbal medicine could modulate the pharmacokinetic behaviour of the co-administered CYP-substrate drug apatinib. Methods Cytochrome P450 enzymes inhibition assays were conducted in human liver microsomes (HLM) by a LC-MS/MS method for simultaneous determination of the oxidative metabolites of eight probe substrates for hepatic CYPs. The modulatory effects of HSYW on the oxidative metabolism of apatinib were investigated in both HLM and rat liver microsomes (RLM). The influences of HSYW on the pharmacokinetic behaviour of apatinib were investigated in rats. Key findings Huosu Yangwei oral liquid inhibited all tested CYPs in human liver preparations, with the IC 50 values ranged from 0.3148 to 2.642 mg/ml. HSYW could also inhibit the formation of two major oxidative metabolites of apatinib in liver microsomes from both human and rat. In-vivo assays demonstrated that HSYW could significantly prolong the plasma half-life of apatinib by 7.4-fold and increase the AUC 0-inf (nMÁh) of apatinib by 43%, when HSYW (10 ml/kg) was co-administered with apatinib (10 mg/kg) in rats. Conclusions Huosu Yangwei oral liquid could inhibit mammalian CYPs and modulated the metabolic half-life of apatinib both in vitro and in vivo.

The Chinese herb Styrax triggers pharmacokinetic herb-drug interactions via inhibiting intestinal CYP3A

“…The inhibitory effects of Styrax or its constituents against CYP3A were assayed by using midazolam as the substrate ( Lee et al, 2013 ; Dunkoksung et al, 2019 ; Fang et al, 2020 ; Tu et al, 2020 ). Briefly, PBS (pH 7.4, 100 mM), Styrax/PTAs/solvent, midazolam, G-6-P, G-6-PDH, MgCl 2 , and enzyme sources (HLMs/RLMs/HIMs/RIMs, 0.1 mg/ml, final concentrations) were added to the EP tube in turn and vortexed, then the samples were pre-incubated for 3 min at 37 °C.…”

Inhibition of drug-metabolizing enzymes by Jingyin granules: implications of herb–drug interactions in antiviral therapy

“…P450 inhibition assays were carried out in 200 μL reaction mixtures, which included phosphate-buffered saline (PBS, 100 mM, pH 7.4), each substrate for a target P450, NADPH-generating system (10 mM of G-6-P, 1.0 unit/mL of G-6-PDH, 1.0 mM of β-NADP + , 4.0 mM of MgCl 2 ), HLMs or RLMs, along with HEJG, or each herbal extract or some major constituents in these herbs [ 32 , 33 ]. Notably, Herba Schizonepetae oil is a key material for preparing Jingyin granules, while water extracts of other individual herbs were used for preparing Jingyin granules.…”

Reversible and Irreversible Inhibition of Cytochrome P450 Enzymes by Methylophiopogonanone A

“…The procedure and in vitro incubation system (200 μL) for P450 inhibition assays were identical to the published literatures (He et al, 2015;Wei et al, 2018;Fang et al, 2020), while the concentrations of the probe substrates as well as the incubation times for each P450 reaction were shown in supplementary materials. Briefly, the reaction was conducted in a mixed system containing PBS (100 mM, pH 7.4), NADPH regeneration system (1.0 mM β-NADP + , 10 mM G-6-P, 1.0 U/mL G-6-PDH, and 4.0 mM MgCl 2 ), HLMs and MOA.…”

“…The mixtures were then centrifuged at 20,000 g for 30 min at 4 °C, while the suspension liquid (100 μL) were diluted with Millipore water (100 μL) and then data were possessed by LC-MS/MS as depicted in Table S2. Time-dependent inhibition tests were conducted according to the previously reported procedure with slight modification (Obach et al, 2007;Fang et al, 2020). Briefly, a mixture containing PBS buffer, NADPH regeneration system (1.0 mM β-NADP + , 10 mM G-6-P, 1.0 U/mL G-6-PDH, and 4.0 mM MgCl 2 ), HLMs and MOA was vortexed for 10 sec.…”