Inhibitory Effect of Lygodium Root on the Cytochrome P450 3A Enzyme in vitro and in vivo

Abstract

Purpose

The aim of the present study was to investigate the interactions of the main components of Lygodium root (ie, p-coumaric acid, acacetin, apigenin, buddleoside and Diosmetin-7-O-β-D-glucopyranoside) with cytochrome P450 3A enzyme activity both in vitro and in vivo.

Methods

In vitro inhibition of drugs was assessed by incubating rat liver microsomes (RLMs) with a typical P450 3A enzyme substrate, midazolam, to determine their 50% inhibitory concentration (IC50) values. For the in vivo study, healthy male Sprague Dawley rats were consecutively administered acacetin or apigenin for 7 days at the dosage of 5 mg/kg after being randomly divided into 3 groups: Group A (control group), Group B (acacetin group) and Group C (apigenin group).

Results

Among the five main components of Lygodium root, only acacetin and apigenin showed inhibitory effects on the cytochrome P450 3A enzyme in vitro. The IC50 values of acacetin and apigenin were 58.46 μM and 8.20 μM, respectively. Additionally, the in vivo analysis results revealed that acacetin and apigenin could systemically inhibit midazolam metabolism in rats. The T_max, AUC_(0-t) and C_max of midazolam in group B and group C were significantly increased (P<0.05), accompanied by a significant decrease in V_z/F and CL_z/F (P<0.05).

Conclusion

Acacetin and apigenin could inhibit the activity of the cytochrome P450 3A enzyme in vitro and in vivo, indicating that herbal drug interactions might occur when taking Lygodium root and midazolam synchronously.

Keywords:

• Lygodium root
• drug–drug interactions
• rat liver microsomes
• midazolam
• metabolism

Acknowledgments

The authors gratefully thank Prof. Dapeng Dai for his helpful writing-review and editing of the manuscript. This work was supported by grants funded by the Natural Science Foundation of Zhejiang and Zhejiang Pharmaceutical Association Joint Foundation (LYY18H280003), the High-Level Talent Training Project of Lishui (2015RC03 and 2018RC18), City-level public welfare technology application research project of Lishui (No. 2016GYX42 and 2017GYX15) and CAMS Innovation Fund for Medical Sciences (2018-I2M-1-002).

Data Sharing Statement

Raw data and figures of the current study are available as a dataset via Mendeley: https://data.mendeley.com/datasets/52gxvdnym2/1.

Disclosure

The authors report no conflicts of interest in this work.