Lotus leaf alkaloid fraction can strongly inhibit CYP2D6 isoenzyme activity.

ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese herbal medicine He-Ye, the leaves of the lotus (Nelumbo nucifera) plant, is traditionally used in China for the treatment of sunstroke, thirst, diarrhea, and fever. Currently, the leaf is used not only as an herbal tea to reduce lipid level and control body weight, but also as a major ingredient in some lipid-lowering Chinese patented medicines. Our previous study demonstrated that the alkaloid fraction (AF) of the herb has a strong inhibitory effect on CYP2D6 isoenzyme activity in vitro. The present study aims to further verify this activity using the in vivo rat model and to explore the inhibitory mechanism on CYP2D6 using human liver microsomes (HLMs).

MATERIALS AND METHODS: After a continuous 7-d oral dose of AF (50mg/kg) or a vehicle, Sprague Dawley rats received a single intravenous dose of dextromethorphan or metoprolol. Blood samples were collected at various time points, and the plasma concentrations of the relevant metabolites dextrorphan and hydroxymetoprolol were assayed by LC-MS/MS for evaluating the effect of AF on their pharmacokinetics and CYP2D6 activity. Dextromethorphan as a probe at different concentrations was incubated with HLMs in an incubation buffer system, in the presence or absence of AF at different concentrations. After incubation, the produced metabolite was assayed.

RESULTS: After being pretreated with AF in rats, the plasma concentrations of dextrorphan and hydroxymetoprolol significantly decreased, with Cmax going from 79.44 to 29.96 and 151.18 to 83.39hng/mL (P<0.05), AUCall from 167.27 to 62.25 and 347.68 to 223.24hng/mL (P<0.05), and AUCinf from 183.39 to 84.76 and 350.59 to 234.57hng/mL (P<0.05), respectively, in comparison with those of untreated rats. The t1/2 of hydroxymetoprolol significantly increased from 1.14 to 1.99h (P<0.05). The in vitro incubation test showed that AF competitively inhibited the CYP2D6, with apparent Ki value of 0.64µg/mL.

CONCLUSIONS: AF can strongly inhibit the activity of CYP2D6 enzyme, as confirmed by in vivo and in vitro models. Possible drug interactions may occur between AF and other medications metabolized by CYP2D6. Thus, caution should be paid when the lotus leaf and its preparations are concurrently administered with conventional medicines.