Baicalin Enhanced Oral Bioavailability of Sorafenib in Rats by Inducing Intestine Absorption

Abstract

Background: Sorafenib (SOR) is an oral, potent, selective, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used as the first-line therapy for advanced hepatocellular carcinoma (HCC). Baicalin (BG) is used as adjuvant therapy for hepatitis, which accounts for the leading cause of the development of HCC, and is commonly coadministered with SOR in clinic. The purpose of the current study was to characterize the pharmacokinetic changes of SOR and the potential mechanism when SOR is administered concomitantly with BG in rats for single and multiple doses.Methods: Parallel randomized pharmacokinetic studies were performed in rats which received SOR (50 mg/kg, i.g.) alone or coadministered with BG (160 mg/kg, i.g.) for single and multiple doses (7 days). Plasma SOR levels were quantified by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Rat liver microsomes (RLMs) which isolated from their livers were analyzed for CYP3A and SOR metabolism activities. The inhibitory effect of BG on the metabolism of SOR was also assessed in pooled human liver microsomes (HLMs). The effects of BG on the intestine absorption behaviors of SOR were assessed in the in situ single-pass rat intestinal perfusion model.Results: Coadministration with BG (160 mg/kg, i.g.) for single or multiple doses significantly increased the Cmax, AUC0–t, and AUC0–∞ of orally administered SOR by 1.68-, 1.73-, 1.70-fold and 2.02-, 1.65-, 1.66- fold in male rats and by 1.85-, 1.68-, 1.68-fold and 1.57-, 1.25-, 1.24- fold in female rats, respectively (p < 0.01 or p < 0.05). In vitro incubation assays demonstrated that there were no significant differences of Km, Vmax, and CLint of 1-OH MDZ and SOR N-oxide in RLMs between control and multiple doses of BG-treated groups. BG has no obvious inhibitory effects on the metabolism of SOR in HLMs. In comparison with SOR alone, combining with BG significantly increased the permeability coefficient (Peff) and absorption rate constant (Ka) of the SOR in situ single-pass rat intestinal perfusion model.Conclusion: Notably enhanced oral bioavailability of SOR by combination with BG in rats may mainly account for BG-induced SOR absorption. A greater understanding of potential DDIs between BG and SOR in rats makes major contributions to clinical rational multidrug therapy in HCC patients. Clinical trials in humans and HCC patients need to be further confirmed in the subsequent study.

Study on the Effect of Pharmaceutical Excipient PEG400 on the Pharmacokinetics of Baicalin in Cells Based on MRP2, MRP3, and BCRP Efflux Transporters

“…Metabolites are also actively transported in and out of the cell by uptake transporters (OATPs) and efflux transporters (BCRPs, MRPs, etc.) in the liver membrane ( Figure 8 a) [ 35 ]. Therefore, the metabolic process of baicalin in the liver is an important link affecting the absorption of baicalin.…”

Pharmacokinetic Interactions between Canagliflozin and Sorafenib or Lenvatinib in Rats

“…Sorafenib is a substrate for efflux transporters, such as P-gp, BCRP, and MRP, and thus, transporter-mediated drug interactions may occur when the substrates, inducers, or inhibitors of transporters are applied simultaneously. On the one hand, some studies have shown that inhibitors, such as verapamil and baicalin [ 43 , 44 ] can significantly increase sorafenib exposure by inhibiting P-gp. On the other hand, 5,7-dimethoxyflavone, an inhibitor of BCRP, can elevate the AUC of sorafenib, possibly by inhibiting BCRP-mediated sorafenib efflux [ 45 ].…”

Novel VEGFR2 inhibitors with thiazoloquinoxaline scaffold targeting hepatocellular carcinoma with lower cardiotoxic impact

“…2- Irradiated mice (8 Gy) received vehicle [IRR]. 3- Irradiated mice treated with Sorafenib (50 mg/ kg body wt./ p.o) 70 for 3 successive days [IRR + sorafenib]. 4- Irradiated mice treated with Compound 4d (50 mg/ kg body wt./ p.o) for 3 successive days, [IRR + cmp 4d].…”