Pharmacokinetics of Nuciferine and N-Nornuciferine, Two Major Alkaloids From Nelumbo nucifera Leaves, in Rat Plasma and the Brain

The leaf of the lotus (Nelumbo nucifera) is a natural plant resource used as both food and herbal medicine (He-Ye) in China. Alkaloids are considered the major bioactive compound of the herb and exhibit various biological activities, including anti-hyperlipidemia, anti-obesity, anti-inflammatory, and anti-hyperuricemic effects. Nuciferine (NF) and N-nuciferine (N-NF) are two major alkaloids found in the herb. In the present work, the plasma and brain pharmacokinetics of the two compounds were investigated after oral and intravenous (i.v.) administration of a lotus leaf alkaloid fraction to SD rats via ultra-performance liquid chromatography coupled with photodiode array detection and brain microdialysis. After oral administration (50 mg/kg), the two compounds NF and N-NF were rapidly absorbed into the blood and reached a mean maximum concentration (C(max)) of 1.71 μg/mL at 0.9 h and 0.57 μg/mL at 1.65 h, respectively. After i.v. administration (10 mg/kg), NF and N-NF were found to have a relatively wide volume of distribution (V(d, λz), 9.48 and 15.17 L/kg, respectively) and slow elimination half-life (t(1/2, λz), 2.09 and 3.84 h, respectively). The oral bioavailability of NF and N-NF was estimated as 58.13% and 79.91%, respectively. After i.v. dosing (20 mg/kg), the two compounds rapidly crossed the blood–brain barrier and reached their C(max) (in unbound form): 0.32 and 0.16 μg/mL at 0.89 and 1.22 h, respectively. Both alkaloids had widespread distribution in the brain, with V(d, λz)/F-values of 19.78 L/kg and 16.17 L/kg, respectively. The mean t(1/2, λz) values of NF and N-NF in the brain were 1.24 and 1.39 h, respectively. These results can help us to better understand the characteristics and neuro-pharmacological effects of the lotus alkaloid fraction.