Pharmacokinetic Effects of Cinnamic Acid, Amygdalin, Glycyrrhizic Acid and Liquiritin on Ephedra Alkaloids in Rats.

Abstract

Ephedra alkaloids, including ephedrine (EP), pseudoephedrine (PEP) and methylephedrine (MEP), are sympathomimetic compounds with known toxicities but many Ephedra (Ephedrae herba) preparations, such as Ephedra decoction, have been clinically applied for centuries. In order to explore the possible detoxification mechanism of Ephedra alkaloids, four representative compounds in Ephedra decoction (cinnamic acid, amygdalin, glycyrrhizic acid and liquiritin) were studied for their pharmacokinetic effects on Ephedra alkaloids in Sprague-Dawley rats. Animals were randomly divided into six groups, with six rats in each. Rats were treated orally with EP-PEP-MEP (20mg/kg EP+20mg/kg PEP+20mg/kg MEP) and different combinations of cinnamic acid (3.03mg/kg), amygdalin (56.97mg/kg), glycyrrhizic acid (12.42mg/kg), liquiritin (3.79mg/kg) with EP-PEP-MEP, and 20mg/kg EP+20mg/kg PEP+20mg/kg MEP+3.03mg/kg cinnamic acid+56.97mg/kg amygdalin+12.42mg/kg glycyrrhizic acid+3.79mg/kg liquiritin. Blood samples (0.5mL) were taken from the orbital sinus venous plexus into heparinized tubes at 5, 10, 20, 30, 45, 60, 90, 120, 180, 240, 300 and 360min(6 rats per time point in each group) following single administration. The concentrations of Ephedra alkaloids in rat plasma were determined using a validated high performance liquid chromatography method. Area under the concentration-time curve from 0 to 360min (AUC0-t ) of EP, PEP and MEP were 666.99, 650.76 and 632.37µg·min/mL, respectively. Maximum plasma concentration (C max) of EP, PEP and MEP were 4.15, 4.08 and 3.59μg/mL, respectively. Mean residence time (MRT) of EP, PEP and MEP were 197.00, 173.97 and 183.87min, respectively, when the rats were treated with EP-PEP-MEP. Cinnamic acid increased the AUC0-t of EP while decreased C max of EP, amygdalin and glycyrrhizic acid increased C max and AUC0-t of EP and PEP, while liquiritin decreased AUC0-t of EP and PEP. The four representative compounds reduced MRT of EP, PEP and MEP, four compounds decreased AUC0-t of MEP. The EP-PEP-MEP+cinnamic acid+amygdalin+glycyrrhizic acid+liquiritin group increased AUC0-t of EP while decreased MRT of EP, increased MRT of PEP while decreased AUC0-t of PEP. The EP-PEP-MEP+cinnamic acid+amygdalin+glycyrrhizic acid+liquiritin group decreased MRT, AUC0-t and C max of MEP. Significant changes in pharmacokinetic parameters of EP, PEP and MEP were observed after oral administration with different combinations. The pharmacokinetic results reported here might provide reference for clinical usage of Ephedra alkaloids.