Pharmacokinetics comparison of seven active components after oral administration of Zhizhu pill using raw and processed Rhizoma Atractylodis Macrocephalae

Abstract

Zhizhu pills (ZZP) is a Traditional Chinese Medicine that has been extensively applied in the treatment of spleen deficiency and constipation for many years. As a commonly used prescription in Traditional Chinese medicine, there had been a controversy over whether to use raw Rhizoma Atractylodis Macrocephalae (RRAM) or Bran-Fired Rhizoma Atractylodis Macrocephalae (BRAM) in ZZP. In this study, a specific, sensitive, fast and accurate liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed to analyze the main active components in ZZP. It was used to determine the compound of Atractylenolide I, Atractylenolide III, Synephrine, Nuciferine, Narirutin, Naringin and Hesperidin in rat various biological matrices (plasma, tissue, urine and feces). The liquiritin was used as the internal standard. All the biological samples were prepared using a simple protein precipitation with acetonitrile and methanol (1:1, V/V). A waters UPLC HSS T3 (100 × 2.1 mm, 1.8 μm) column was used in this research. The mobile phase consisting of 0.1 % aqueous formic acid (A)-0.1 % formic acid in acetonitrile (B) was employed to separate seven components from endogenous interferences. The components were detected with a triple quadrupole mass spectrometer using positive and negative ion multiple reaction monitoring (MRM) mode. The newly developed method was successfully applied to investigate the pharmacokinetics, tissue distribution and excretion of seven components after intragastric administration ZZP which was composed with RRAM or BRAM in rats. The pharmacokinetic results indicated that seven active components can be quickly absorbed and had undergone the enterohepatic circulation. It could also indicate higher C_max of Nuciferine, Narirutin, Naringin and Hesperidin in the plasma after intragastric administration ZZP compose of BRAM than RRAM. In tissue distribution, the seven active components in ZZP were mainly distributed in the stomach, large intestine and small intestine. It could indicate a lower C_max of Atractylenolide I, Atractylenolide III in the stomach, large intestine and small intestine after intragastric administration ZZP compose of BRAM compared to RRAM. It could also indicate higher Cmax of Narirutin, Naringin, and Synephrine in the stomach, large intestine and small intestine after intragastric administration ZZP compose of BRAM than RRAM. The results of the excretion study showed that the total urinary excretion rate of the 7 active components at 48 h was lower after intragastric administration ZZP compose of BRAM than RRAM. Meanwhile, the total fecal excretion rate of the 7 active components was higher after intragastric administration ZZP compose of BRAM than RRAM. The pharmacokinetics, tissue distribution and excretion characteristics of seven active components in ZZP were first revealed. It also used to compare the difference of ZZP compose of BRAM than RRAM in the pharmacokinetics perspective. It will provide references for the rationality application of the ZZP in clinical.