The Impact of Baohuoside I on the Metabolism of Tofacitinib in Rats

Abstract

Purpose

To study the potential drug–drug interactions between tofacitinib and baohuoside I and to provide the scientific basis for rational use of them in clinical practice.

Methods

A total of eighteen Sprague-Dawley rats were randomly divided into three groups: control group, single-dose group (receiving a single dose of 20 mg/kg of baohuoside I), and multi-dose group (receiving multiple doses of baohuoside I for 7 days). On the seventh day, each rat was orally administered with 10 mg/kg of tofacitinib 30 minutes after giving baohuoside I or vehicle. Blood samples were collected and determined using UPLC-MS/MS. In vitro effects of baohuoside I on tofacitinib was investigated in rat liver microsomes (RLMs), as well as the underlying mechanism of inhibition. The semi-inhibitory concentration value (IC₅₀) of baohuoside I was subsequently determined and its inhibitory mechanism against tofacitinib was analyzed. Furthermore, the interactions between baohuoside I, tofacitinib and CYP3A4 were explored using Pymol molecular docking simulation.

Results

The administration of baohuoside I orally has been observed to enhance the area under the concentration-time curve (AUC) of tofacitinib and decrease the clearance (CL). The observed disparity between the single-dose and multi-dose groups was statistically significant. Furthermore, our findings suggest that the impact of baohuoside I on tofacitinib metabolism may be a mixture of non-competitive and competitive inhibition. Baohuoside I exhibit an interaction with arginine (ARG) at position 106 of the CYP3A4 enzyme through hydrogen bonding, positioning itself closer to the site of action compared to tofacitinib.

Conclusion

Our study has demonstrated the presence of drug–drug interactions between baohuoside I and tofacitinib, which may arise upon pre-administration of tofacitinib. Altogether, our data indicated that an interaction existed between tofacitinib and baohuoside I and additional cares might be taken when they were co-administrated in clinic.

Keywords:

• drug–drug interaction
• pharmacokinetics
• tofacitinib
• baohuoside I
• cytochrome P450

Acknowledgments

This work was supported by the Public Welfare Technology Research Funding Project of Zhejiang (LTGY24H100002 and LGF21H310001), the Public Welfare Technology Research Funding Project of Lishui (2021SJZC022, 2021SJZC023, 2020GYX23, 2022SJZC079, 2023GYX04, 2022GYX24 and 2023GYX18), the Key Research and Development Project of Lishui (2021ZDYF13, 2021ZDYF15, and 2023zdyf15), Medical and health science and technology plan project Zhejiang province (2022RC302, 2022RC303 and 2023RC312).

Disclosure

The authors have no conflicts of interest and no disclosures to declare.