Dataset Information

Multi-Component Comparative Pharmacokinetics in Rats After Oral Administration of Fructus aurantii Extract, Naringin, Neohesperidin, and Naringin-Neohesperidin.

ABSTRACT: Citrus × aurantium L., Chinese name: Fructus Aurantii (FA) has been largely used as Qi-invigorating herb in China for centuries. The main components (meranzin hydrate, naringin, neohesperidin, meranzin, nobiletin) have good physiological activity with relatively high abundance in FA. Few multi-component comparative pharmacokinetics are simultaneously accessible for the flavone glycosides, polymethoxy flavones, and coumarins in FA. In this work, a reliable and rapid ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was established and validated to determine the five ingredients in the SD rat plasma, and further applied to the pharmacokinetic studies after oral administration of monomer, drugs in compatibility, and FA extract. After hydrolysis with ?-glucuronidase and sulfatase, the concentration of naringin and neohesperidin in rat plasma were expressed respectively by the total concentration of naringenin and hesperitin which was determined by UPLC-MS/MS. Double-peak phenomenon was observed for naringin and neohesperidin, which may be due to the enterohepatic circulation or multiple site absorption of the two flavone glycosides. Meranzin hydrate and meranzin (coumarins) were absorbed rapidly (Tmax, about 1.0 h) but eliminated slowly (t1/2z exceeds 6.5 h). Nobiletin, a typical polymethoxy flavone, was also rapidly absorbed according to Tmax and AUC(0-t). DAS 3.1 software suggests the pharmacokinetic profiles of the five components in rats be depicted as a two-compartment pharmacokinetic model. There were significant differences in pharmacokinetic parameters for naringenin and hesperetin between the compatibility, FA extract group vs monomer group: ? remarkable increases in the values of AUC(0-?), AUC(0-t) and Cmax; ? obvious decrease of CLZ/F; and ? longer tmax and t1/2z. The results suggest that compatibility can promote mutual absorption and affect the elimination behaviors.

SUBMITTER: Yuan J

PROVIDER: S-EPMC7319089 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Multi-Component Comparative Pharmacokinetics in Rats After Oral Administration of <i>Fructus aurantii</i> Extract, Naringin, Neohesperidin, and Naringin-Neohesperidin.

Yuan Jinbin J Wei Feiting F Luo Xizhen X Zhang Min M Qiao Rifa R Zhong Minyong M Chen Haifang H Yang Wuliang W

Frontiers in pharmacology 20200619

Citrus × aurantium L., Chinese name: <i>Fructus Aurantii</i> (FA) has been largely used as Qi-invigorating herb in China for centuries. The main components (meranzin hydrate, naringin, neohesperidin, meranzin, nobiletin) have good physiological activity with relatively high abundance in FA. Few multi-component comparative pharmacokinetics are simultaneously accessible for the flavone glycosides, polymethoxy flavones, and coumarins in FA. In this work, a reliable and rapid ultra-high performance ...[more]

PMID: 32636752

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Project description:The clinical use of Polygonum multiflorum Thunb (PM) has been restricted or banned in many countries, due to its hepatotoxic adverse effects. Its toxicity research has become a hot topic. So far, the pharmacokinetic studies of PM, focusing on prototype compounds such as 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), emodin, and physcion, have been considered the main basis of pharmacodynamic material or of toxic effect. However, pharmacokinetic studies of its phase II metabolites have not yet been reported, mainly because the quantifications of such metabolites are difficult to do without the reference substance. In addition, pharmacokinetic studies on different pathological models treated with PM have also not been reported. On the other hand, toxic effects of PM have been reported in patients diagnosed with different liver pathologies. In the present work, a simultaneous quantitation method for eight prototypes components of PM and their five phase II metabolites has been performed by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and used for the pharmacokinetic study of PM in two different liver pathological models in rats (normal, alpha-naphthylisothiocyanate (ANIT), and carbon tetrachloride (CCl4)). The results showed that the main blood-entering components of PM are TSG, emodin, physcion, emodin-8-O-β⁃D⁃glucoside (E-Glu), physcion-8-O-β⁃D⁃glucoside (P-Glu), aloe-emodin, gallic acid, resveratrol and catechin, among which TSG, emodin, and catechin were primary metabolized in phase II, while resveratrol was converted to all phase II metabolites, and the others were metabolized as drug prototypes. Meanwhile, their pharmacokinetic parameters in the different models also exhibited significant differences. For instance, the AUC (0-∞) values of the TSG prototype and its phase II metabolites were higher in the ANIT group, followed by CCl4 group and the normal group, while the AUC (0-∞) values of the emodin prototype and its phase II metabolites were higher in the CCl4 group. To further illustrate the reasons for the pharmacokinetic differences, bilirubin metabolizing enzymes and transporters in the liver were measured, and the correlations with the AUC of the main compounds were analyzed. TSG and aloe-emodin have significant negative correlations with UGT1A1, BSEP, OATP1A4, OCT1, NTCP, MRP2 and MDR1 (p < 0.01). These data suggest that when the expression of metabolic enzymes and transporters in the liver is inhibited, the exposure levels of some components of PM might be promoted in vivo.

Dataset Information

Multi-Component Comparative Pharmacokinetics in Rats After Oral Administration of Fructus aurantii Extract, Naringin, Neohesperidin, and Naringin-Neohesperidin.

Publications

Multi-Component Comparative Pharmacokinetics in Rats After Oral Administration of <i>Fructus aurantii</i> Extract, Naringin, Neohesperidin, and Naringin-Neohesperidin.

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