The effects of triptolide on the pharmacokinetics of sorafenib in rats and its potential mechanism

作者：Wang, Xianming; Zhang, Xin; Liu, Fei; Wang, Minghai^*; Qin, Shiyong^*

来源：Pharmaceutical Biology, 2017, 55(1): 1863-1867.

DOI：10.1080/13880209.2017.1340963

• CYP3A4
• herb-drug interaction
• P-gp

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 (10mg/kg) on the pharmacokinetics of different doses of sorafenib (20, 50 and 100mg/kg) in rats, and blood samples were collected within 48h 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 C-max (low dose: 72.388.76 versus 49.15 +/- 5.46ng/mL; medium dose: 178.65 +/- 21.05 versus 109.31 +/- 14.17ng/mL; high dose: 332.81 +/- 29.38 versus 230.86 +/- 9.68ng/mL) of sorafenib at different doses increased significantly with the pretreatment of triptolide, and while the oral clearance rate of sorafenib decreased. The t(1/2) of sorafenib increased significant (p<0.05) from 9.02 +/- 1.16 to 12.17 +/- 2.95h 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 +/- 4.43L/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.

• 出版日期2017-6-14
• 单位山东大学; 山东省千佛山医院