The oral bioavailability, excretion and cytochrome P450 inhibition properties of epiberberine: an in vivo and in vitro evaluation

Abstract

Epiberberine (EPI) is a novel and potentially effective therapeutic and preventive agent for diabetes and cardiovascular disease. To evaluate its potential value for drug development, a specific, sensitive and robust high-performance liquid chromatography-tandem mass spectrometry assay for the determination of EPI in rat biological samples was established. This assay was used to study the pharmacokinetics, bioavailability and excretion of EPI in rats after oral administration. In addition, a cocktail method was used to compare the inhibition characteristics of EPI on cytochrome P450 (CYP450) isoforms in human liver microsomes (HLMs) and rat liver microsomes (RLMs). The results demonstrated that EPI was rapidly absorbed and metabolized after oral administration (10, 54 or 81 mg/kg) in rats, with Tmax of 0.37–0.42 h and T1/2 of 0.49–2.73 h. The Cmax and area under the curve values for EPI increased proportionally with the dose, and the oral absolute bioavailability was 14.46%. EPI was excreted mainly in bile and feces, and after its oral administration to rats, EPI was eliminated predominantly by the kidneys. A comparison of the current half-maximal inhibitory concentration and Ki values revealed that EPI demonstrated an obvious inhibitory effect on CYP2C9 and CYP2D6. Furthermore, its effect was stronger in HLM than in RLM, more likely to be a result of noncompetitive inhibition.

Switching a Xanthine Oxidase Inhibitor to a Dual-Target Antagonist of P2Y1 and P2Y12 as an Oral Antiplatelet Agent with a Wider Therapeutic Window in Rats than Ticagrelor

“…CYP450-mediated drug–drug interaction is one of the important reasons for the dropout of drug candidates during new drug development . Therefore, testing for drug–drug interaction potential of new chemical entities is essential for developing a novel drug. − As a result, compounds 24w and 25w were selected to further evaluate their in vitro inhibitory potential of major CYP450 enzymes including CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 in a CYP450 inhibition cocktail assay, and the results are summarized in Table . Indeed, compound 25w was found to show no significant inhibition against these CYP450 isoforms at 10 μM, which indicated that its IC 50 value against these major CYP450 isoforms was greater than 10 μM.…”

Systems Pharmacology-Based Method to Assess the Mechanism of Action of Weight-Loss Herbal Intervention Therapy for Obesity

“…Obacunone, as one of the oxygenated triterpenoids of Huang Lian, has been confirmed to be beneficial against obesity through the Takeda G-protein receptor 5 (TGR5) and peroxisome proliferator–activated receptor gamma (PPARγ) pathway (Horiba et al, 2015). The protoberberine alkaloid epiberberine (OB = 43.09% and DL = 0.78) from Huang Lian is a potential preventive and therapeutic agent for diabetes (Chen et al, 2018). Calycosin is the major active component in Huang Qi and exhibits beneficial effects against high-fat diet-induced nonalcoholic fatty liver disease (Duan et al, 2018).…”

Toxicity and toxicokinetics of the ethanol extract of Zuojin formula

“…Berberine and other alkaloids, including jatrorrhizine and palmatine, can be metabolized by CYP3A4, CYP1A2 and CYP2D6 [27][28][29][30]. These enzymes can also be inhibited by epiberberine and berberine [31][32][33][34]. Thus, there might be drug-drug interactions (DDIs) between these alkaloids, A sex difference was also observed for the plasma concentrations of the compounds.…”