Effect of major components of Tripterygium wilfordii Hook. f on the uptake function of organic anion transporting polypeptide 1B1.

Organic anion transporting polypeptide 1B1 (OATP1B1), which is specifically expressed at the basolateral membrane of human hepatocytes, is well recognized as the key determinant in the pharmacokinetics of a wide variety of drugs and considered as an important drug-drug interaction (DDI) site. Triptergium wilfordii Hook. f. (TWHF) is a traditional Chinese medicine that has a long history in treating diseases and more pharmacological effects were demonstrated recently. Components of TWHF mainly belong to the groups of alkaloids, diterpenoids, and triterpenoids. However, whether TWHF constituents are involved in herb-drug interaction (HDI) remains largely unknown. In the present study, we investigated the effect of four major components of TWHF, i.e. Triptolide (TPL), Celastrol (CL), and two alkaloids Wilforine (WFR) and Wilforgine (WFG) on the function of OATP1B1. It was found that co-incubation of these compounds greatly inhibited the uptake function of OATP1B1, with WFG (IC50 = 3.63 ± 0.61 μM) and WFR (IC50 = 3.91 ± 0.30 μM) showing higher inhibitory potency than TPL (IC50 = 184 ± 36 μM) and CL (IC50 = 448 ± 81 μM). Kinetic analysis revealed that co-incubation of WFG or WFR led to the reduction of both Km and Vmax of the DCF uptake. On the other hand, pre-incubation of WFG or WFR increased Km value of OATP1B1; while CL affected both Km and Vmax. In conclusion, co- and pre-incubation of the tested TWHF components inhibited OATP1B1 activity in different manners. Although co-incubation of WFG and WFR did not seem to directly compete with the substrates, pre-incubation of these alkaloids may alter the substrate-transporter interaction.