Phyllanthus amarus Schum. & Thonn. has been used for the treatment of various diseases. Previous in vitro study in human liver microsome demonstrated the inhibitory activity of P. amarus extract on CYP3A4, an enzyme responsible for various drug metabolism. The objective of this study was to evaluate the effect of P. amarus ethanolic extract on the pharmacokinetics of midazolam, a CYP3A4 probe drug, in rabbits. Midazolam plasma concentration time-profiles (0-8 h) after a single oral dose of 10 mg/kg midazolam were examined in rabbits receiving P. amarus extract compared to control. In treatment group, P. amarus extract (500 mg/kg) was orally administered for 7 days and on the experiment day prior to midazolam administration. The results showed that pretreatment with P. amarus significantly increased the mean maximum concentration (Cmax), time to reach maximum concentration (Tmax), area under curve (AUC0-8), and elimination half-life (T1/2) (2.9-, 1.6-, 2.8-, and 1.4-fold, respectively) compared with control group receiving a single oral dose of midazolam. The results suggest that P. amarus extract inhibits midazolam metabolism in rabbits probably by inhibition of CYP3A which is the enzyme responsible for midazolam metabolism. Therefore, coadministration of P. amarus and drugs which are CYP3A substrates may increase plasma drug concentration leading to serious side effects. Thus, concern over the clinical relevance of herb-drug interaction between P. amarus and CYP3A substrates should be warranted. However, further investigation is needed to be performed in human to reveal the clinically significant potential of these herb-drug interactions.
