Phyllanthus amarus has long been used as a herbal medicine in several countries. Phytochemicals in herbal medicine may interact with cytochromes P450 (CYP) and thus raise the potential of herb-drug interactions; therefore, the inhibitory effects of P. amarus and its major phytochemicals phyllanthin and hypophyllanthin on CYP isoforms were determined using human liver microsomes and selective substrates. Both ethanolic and aqueous extracts of P. amarus inhibited CYP1A2, CYP2D6, CYP2E1 and CYP3A4 in a dose-dependent manner. Compared to known CYP3A inhibitors, the IC(50) values of the ethanolic and aqueous extracts on testosterone 6β-hydroxylation were higher than that of ketoconazole but were lower than those of erythromycin and clarithromycin. Both extracts were weak inhibitors of CYP1A2, CYP2D6 and CYP2E1. In addition, phyllanthin and hypophyllanthin were potent mechanism-based inhibitors of CYP3A4 with K(I) values of 1.75 ± 1.20 µM and 2.24 ± 1.84 µM and k(inact) values of 0.18 ± 0.05 min(-1) and 0.15 ± 0.06 min(-1), respectively. The k(inact)/K(I) ratios of these lignans were higher than those reported for some therapeutic drugs that act as mechanism-based inhibitors of CYP3A4. These results suggest that co-administration of P. amarus with drugs that are metabolized by CYP3A4 may potentially result in herb-drug interactions.

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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. 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. 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. 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.

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