Simultaneous Determination of Luteoloside, Apigetrin, And Hesperidin In Rat Plasma By UHPLC-MS/MS: Application to A Comparative Pharmacokinetic Investigation After Oral Administration Of Schizonepeta Tenuifolia Aqueous Extract With And Without Its Volatile Oil

Background: Schizonepeta tenuifolia Briq. (ST) has been used as an aromatic exterior-releasing medicine in clinical practice for thousands of years in China. Previous researches have revealed both volatile oil (STVO) and aqueous extract (STAE) from ST showed significant pharmacological activities. However, the influence between each other was still unknown. Methods: This study was designed to compare the pharmacokinetic profiles of three main flavonoids (luteoloside, apigetrin, and hesperidin) in STAE to illustrate the influence of STVO. So, an ultra-flow liquid chromatography-tandem mass spectrometry (UHPLC-MS) method was established to quantitatively analyze the three absorbed ingredients in the plasma of healthy rats. Biological samples were analyzed on an Agilent Eclipse Plus C18 column (3.0 mm × 150 mm, 3.5 μm) with gradient mobile phase (containing 0.2% formic acid and acetonitrile) at a flow rate of 0.8 mL/min. All the analytes and quercitrin (IS) were investigated with an electrospray ionization source (ESI) using multiple-reaction monitoring (MRM) in negative ionization mode. Results: This quantitative method showed good linearities (r ≥0.9995) and the lower limits of quantification were 0.590~1.19 ng/ml. The intra- and inter-day precisions ranged 3.47~10.45% and 4.29~11.28% for the three analytes. The mean extraction recoveries were in the range of 77.41~109.79% and the average matrix effects were within 83.41~112.67%. The validated method has been fully applied to compare the pharmacokinetic parameters of the three flavonoid glycosides in rat plasma after oral administration of STAE and STAE+STVO. In comparison of luteoloside, apigetrin, and hesperidin in STAE group, it was found that different degree of increasing existed for the time to reach the maximum concentration (Tmax), elimination half-life time (T1/2), the area under the concentration curves (AUC0→t and AUC0→∞) and the maximum concentrations (Cmax) in STAE+STVO group. Conclusions: As can be seen from above, STVO could improve the absorption and bioavailability of the three analytes. These findings would provide some active and strong basis of safe clinical application for ST and further exploitation for STVO from the perspective of drug-drug interaction.