Comparative Studies on Multi-Component Pharmacokinetics of Polygonum multiflorum Thunb Extract After Oral Administration in Different Rat Models
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'-tetrahydroxysti...
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Frontiers Media S.A.
2021-06-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.655332/full |
| _version_ | 1818892014953955328 |
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| author | Ninghui Ma Yong Zhang Liyan Sun Yuan Zhao Yue Ding Yue Ding Tong Zhang Tong Zhang |
| author_facet | Ninghui Ma Yong Zhang Liyan Sun Yuan Zhao Yue Ding Yue Ding Tong Zhang Tong Zhang |
| author_sort | Ninghui Ma |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-19T17:49:58Z |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-12-19T17:49:58Z |
| publishDate | 2021-06-01 |
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| spelling | doaj.art-74da450b2fed4dc7a6b42c714781658f2022-12-21T20:11:57ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-06-011210.3389/fphar.2021.655332655332Comparative Studies on Multi-Component Pharmacokinetics of Polygonum multiflorum Thunb Extract After Oral Administration in Different Rat ModelsNinghui Ma0Yong Zhang1Liyan Sun2Yuan Zhao3Yue Ding4Yue Ding5Tong Zhang6Tong Zhang7School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaExperiment Center of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaSchool of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaExperiment Center for Science and Technology, Shanghai University of Traditional Chines Medicine, Shanghai, ChinaSchool of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaExperiment Center of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaSchool of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaExperiment Center of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaThe 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.https://www.frontiersin.org/articles/10.3389/fphar.2021.655332/fullANITCCl4pharmacokineticsbilirubin metabolism enzymemetabolic transporterpolygonum multiflorum thunb |
| spellingShingle | Ninghui Ma Yong Zhang Liyan Sun Yuan Zhao Yue Ding Yue Ding Tong Zhang Tong Zhang Comparative Studies on Multi-Component Pharmacokinetics of Polygonum multiflorum Thunb Extract After Oral Administration in Different Rat Models Frontiers in Pharmacology ANIT CCl4 pharmacokinetics bilirubin metabolism enzyme metabolic transporter polygonum multiflorum thunb |
| title | Comparative Studies on Multi-Component Pharmacokinetics of Polygonum multiflorum Thunb Extract After Oral Administration in Different Rat Models |
| title_full | Comparative Studies on Multi-Component Pharmacokinetics of Polygonum multiflorum Thunb Extract After Oral Administration in Different Rat Models |
| title_fullStr | Comparative Studies on Multi-Component Pharmacokinetics of Polygonum multiflorum Thunb Extract After Oral Administration in Different Rat Models |
| title_full_unstemmed | Comparative Studies on Multi-Component Pharmacokinetics of Polygonum multiflorum Thunb Extract After Oral Administration in Different Rat Models |
| title_short | Comparative Studies on Multi-Component Pharmacokinetics of Polygonum multiflorum Thunb Extract After Oral Administration in Different Rat Models |
| title_sort | comparative studies on multi component pharmacokinetics of polygonum multiflorum thunb extract after oral administration in different rat models |
| topic | ANIT CCl4 pharmacokinetics bilirubin metabolism enzyme metabolic transporter polygonum multiflorum thunb |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.655332/full |
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