Effects of Phyllanthus amarus on the pharmacokinetics of midazolam and cytochrome P450 activities in rats

Abstract

1. Phyllanthus amarus, a commonly used medicinal herb, was investigated for possible herb–drug interactions. The effect on CYP3A-mediated drug metabolism in rats after single dose administration of P. amarus extract was investigated using midazolam (MDZ) as a probe substrate. The effect of multiple dose administration of P. amarus extract on activity and expression of various CYP isoforms were studied.

2. Oral administration of P. amarus extract (800 mg/kg) 1 h before oral MDZ increased the C_max and AUC_0–-∞ of MDZ by 3.9- and 9.6-fold and decreased the clearance by 12%, but did not alter the pharmacokinetics of intravenous MDZ.

3. Daily administration of P. amarus extract (200 or 800 mg/kg/day) for 15 days in rats increased the activity and expression of CYP3A and CYP2B1/2. In contrast, the activities and expressions of CYP1A, CYP2C and CYP2E1 were not significantly changed.

4. The dual effects of P. amarus extract on CYP enzymes were demonstrated. Single dose administration of the extract increased oral bioavailability of MDZ through inhibition of intestinal CYP3A whereas repeated administration of the extract slightly induced hepatic CYP3A and CYP2B1/2 in rats, which suggested that herb–drug interactions by P. amarus may potentially occur via CYP3A and 2B.

Keywords::

• Herb–drug interaction
• P. amarus
• CYP3A
• Phyllanthus
• cytochromes P450
• CYP

This work was supported by the Thai Traditional Medicine Development Foundation; the Office of the Higher Education Commission; the National Research Council of Thailand; and Khon Kaen University, Thailand. Financial support from the Thailand Research Fund through the Royal Golden Ph.D. Program to Wichittra Tassaneeyakul and Theerada Taesotikul (TT) (PHD/0118/2549) is acknowledged. Kanazawa University is also acknowledged for partial support of the living allowance for TT during her stay in Japan. We also thank Prof. Yukifumi Nawa and Prof. James A. Will, for valuable comments and suggestions on the manuscript.

Declaration of interest

This work was supported by the Thai Traditional Medicine Development Foundation; the Office of the Higher Education Commission; the National Research Council of Thailand; and Khon Kaen University, Thailand. Financial support was from the Thailand Research Fund through the Royal Golden Ph.D. Program to Wichittra Tassaneeyakul and Theerada Taesotikul (TT) (PHD/0118/2549). Kanazawa University gave partial support of the living allowance for TT during her stay in Japan.