Abstract
Context: Combining sorafenib with triptolide could inhibit tumour growth with greater efficacy than single-agent treatment. However, their herb–drug interaction remains unknown.Objective: This study investigates the herb–drug interaction between triptolide and sorafenib.Materials and methods: The effects of triptolide (10 mg/kg) on the pharmacokinetics of different doses of sorafenib (20, 50 and 100 mg/kg) in rats, and blood samples were collected within 48 h and evaluated using LC-MS/MS. The effects of triptolide on the absorption and metabolism of sorafenib were also investigated using Caco-2 cell monolayer model and rat liver microsome incubation systems.Results: The results showed that the Cmax (low dose: 72.38 ± 8.76 versus 49.15 ± 5.46 ng/mL; medium dose: 178.65 ± 21.05 versus 109.31 ± 14.17 ng/mL; high dose: 332.81 ± 29.38 versus 230.86 ± 9.68 ng/mL) of sorafenib at different doses increased significantly with the pretreatment of triptolide, and while the oral clearance rate of sorafenib decreased. The t1/2 of sorafenib increased significant (p < 0.05) from 9.02 ± 1.16 to 12.17 ± 2.95 h at low dose with the pretreatment of triptolide. Triptolide has little effect on the absorption of sorafenib in Caco-2 cell transwell model. However, triptolide could significantly decrease the intrinsic clearance rate of sorafenib from 51.7 ± 6.37 to 32.4 ± 4.43 μL/min/mg protein in rat liver microsomes.Discussion and conclusions: These results indicated that triptolide could change the pharmacokinetic profiles of sorafenib in rats; these effects might be exerted via decreasing the intrinsic clearance rate of sorafenib in rat liver.
Highlights
Sorafenib is an orally active tyrosine kinase inhibitor, which has been approved for the treatment of renal and hepatocellular carcinoma (Abdel-Rahman 2013; Abdulghani et al 2013; Ahmadi et al 2014)
The absorption of sorafenib in small-intestinal mucosa was mainly mediated by P-glycoprotein (P-gp), and sorafenib was mainly metabolized by cytochrome P450 3A4 (CYP3A4) and uridine diphosphate glucuronosyl transferase 1A9 (UGT1A9) (Doi et al 2011; Zimmerman et al 2012; Gillani et al 2014)
The results showed that the Cmax and area under the plasma concentration–time curve (AUC)(0–t) of sorafenib at different doses increased significantly, and while the oral clearance rate of sorafenib decreased with the pretreatment of triptolide
Summary
Sorafenib is an orally active tyrosine kinase inhibitor, which has been approved for the treatment of renal and hepatocellular carcinoma (Abdel-Rahman 2013; Abdulghani et al 2013; Ahmadi et al 2014). Research indicates that sorafenib could inhibit tumour cell proliferation by targeting Raf/mitogen-activated protein kinase or extracellular signal-regulated kinase, and exert antiangiogenic effects by targeting vascular endothelial growth factor receptor-1/-2/-3 and platelet-derived growth factor receptor-b tyrosine kinases (Bhatt and Ganti 2014; Booth et al 2014; Brown et al 2014; Chen et al 2014). Some research articles have indicated that the combination of sorafenib and triptolide is superior to single-drug treatment in increasing cell death and apoptosis, and combining sorafenib with triptolide could inhibit tumour growth with greater efficacy than single-agent treatments (Alsaied et al 2014). To the best of our knowledge, there is little data available for the effects of triptolide on the pharmacokinetics of sorafenib
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