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Research ArticleArticle

Combined Contribution of Increased Intestinal Permeability and Inhibited Deglycosylation of Ginsenoside Rb1 in the Intestinal Tract to the Enhancement of Ginsenoside Rb1 Exposure in Diabetic Rats after Oral Administration

Can Liu, Mengyue Hu, Haifang Guo, Mian Zhang, Ji Zhang, Feng Li, Zeyu Zhong, Yang Chen, Ying Li, Ping Xu, Jia Li, Li Liu and Xiaodong Liu
Drug Metabolism and Disposition November 2015, 43 (11) 1702-1710; DOI: https://doi.org/10.1124/dmd.115.064881
Can Liu
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (C.L., M.H., M.Z., J.Z., F.L., Z.Z., Y.C., Y.L., P.X., J.L., L.L., X.L.); Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida (C.L.); and Bioanalytical and Pharmacokinetics/Toxicokinetics Center, Jiangsu Tripod Preclinical Research Laboratories Inc., Nanjing, China (H.G.)
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Mengyue Hu
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (C.L., M.H., M.Z., J.Z., F.L., Z.Z., Y.C., Y.L., P.X., J.L., L.L., X.L.); Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida (C.L.); and Bioanalytical and Pharmacokinetics/Toxicokinetics Center, Jiangsu Tripod Preclinical Research Laboratories Inc., Nanjing, China (H.G.)
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Haifang Guo
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (C.L., M.H., M.Z., J.Z., F.L., Z.Z., Y.C., Y.L., P.X., J.L., L.L., X.L.); Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida (C.L.); and Bioanalytical and Pharmacokinetics/Toxicokinetics Center, Jiangsu Tripod Preclinical Research Laboratories Inc., Nanjing, China (H.G.)
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Mian Zhang
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (C.L., M.H., M.Z., J.Z., F.L., Z.Z., Y.C., Y.L., P.X., J.L., L.L., X.L.); Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida (C.L.); and Bioanalytical and Pharmacokinetics/Toxicokinetics Center, Jiangsu Tripod Preclinical Research Laboratories Inc., Nanjing, China (H.G.)
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Ji Zhang
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (C.L., M.H., M.Z., J.Z., F.L., Z.Z., Y.C., Y.L., P.X., J.L., L.L., X.L.); Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida (C.L.); and Bioanalytical and Pharmacokinetics/Toxicokinetics Center, Jiangsu Tripod Preclinical Research Laboratories Inc., Nanjing, China (H.G.)
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Feng Li
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (C.L., M.H., M.Z., J.Z., F.L., Z.Z., Y.C., Y.L., P.X., J.L., L.L., X.L.); Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida (C.L.); and Bioanalytical and Pharmacokinetics/Toxicokinetics Center, Jiangsu Tripod Preclinical Research Laboratories Inc., Nanjing, China (H.G.)
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Zeyu Zhong
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (C.L., M.H., M.Z., J.Z., F.L., Z.Z., Y.C., Y.L., P.X., J.L., L.L., X.L.); Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida (C.L.); and Bioanalytical and Pharmacokinetics/Toxicokinetics Center, Jiangsu Tripod Preclinical Research Laboratories Inc., Nanjing, China (H.G.)
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Yang Chen
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (C.L., M.H., M.Z., J.Z., F.L., Z.Z., Y.C., Y.L., P.X., J.L., L.L., X.L.); Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida (C.L.); and Bioanalytical and Pharmacokinetics/Toxicokinetics Center, Jiangsu Tripod Preclinical Research Laboratories Inc., Nanjing, China (H.G.)
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Ying Li
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (C.L., M.H., M.Z., J.Z., F.L., Z.Z., Y.C., Y.L., P.X., J.L., L.L., X.L.); Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida (C.L.); and Bioanalytical and Pharmacokinetics/Toxicokinetics Center, Jiangsu Tripod Preclinical Research Laboratories Inc., Nanjing, China (H.G.)
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Ping Xu
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (C.L., M.H., M.Z., J.Z., F.L., Z.Z., Y.C., Y.L., P.X., J.L., L.L., X.L.); Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida (C.L.); and Bioanalytical and Pharmacokinetics/Toxicokinetics Center, Jiangsu Tripod Preclinical Research Laboratories Inc., Nanjing, China (H.G.)
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Jia Li
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (C.L., M.H., M.Z., J.Z., F.L., Z.Z., Y.C., Y.L., P.X., J.L., L.L., X.L.); Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida (C.L.); and Bioanalytical and Pharmacokinetics/Toxicokinetics Center, Jiangsu Tripod Preclinical Research Laboratories Inc., Nanjing, China (H.G.)
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Li Liu
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (C.L., M.H., M.Z., J.Z., F.L., Z.Z., Y.C., Y.L., P.X., J.L., L.L., X.L.); Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida (C.L.); and Bioanalytical and Pharmacokinetics/Toxicokinetics Center, Jiangsu Tripod Preclinical Research Laboratories Inc., Nanjing, China (H.G.)
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Xiaodong Liu
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (C.L., M.H., M.Z., J.Z., F.L., Z.Z., Y.C., Y.L., P.X., J.L., L.L., X.L.); Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida (C.L.); and Bioanalytical and Pharmacokinetics/Toxicokinetics Center, Jiangsu Tripod Preclinical Research Laboratories Inc., Nanjing, China (H.G.)
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Abstract

Panax ginseng is becoming a promising antidiabetic herbal medication. As the main active constituents of Panax ginseng, ginsenosides are well known, poorly absorbed chemicals. However, the pharmacokinetic behavior of ginsenosides under diabetic conditions is not fully understood. This study aimed to explore the alterations and potential mechanisms of pharmacokinetic behavior of ginsenoside Rb1 in diabetic rats compared with normal rats and rats fed a high-fat diet. Systemic exposure (area under the concentration-time curve extrapolated from zero to infinity) was significantly increased in diabetic rats after oral administration of Rb1. Oral bioavailability of Rb1 was significantly higher in diabetic rats (2.25%) compared with normal rats (0.90%) and rats fed a high-fat diet (0.78%). Further studies revealed that increased Rb1 exposure in diabetic rats may be mainly attributed to increased Rb1 absorption via the intestine and inhibited Rb1 deglycosylation by the intestinal microflora. Neither metabolic enzymes nor drug transporters displayed appreciable effects on Rb1 disposition. The transport of paracellular markers (fluorescein sodium and fluorescein isothiocyanate-dextran of 4 kDa) as well as Rb1 itself across the Caco-2 monolayer cultured with diabetic serum was promoted, demonstrating that increased paracellular permeability of the Caco-2 monolayer may benefit intestinal Rb1 absorption. In addition, Rb1 exposure was decreased in diabetic rats after Rb1 intravenous administration, which may result from increased Rb1 urinary excretion. In conclusion, Rb1 oral exposure was significantly increased under diabetic conditions, which is of positive significance to clinical treatment. The potential mechanism may be associated with the combined contribution of increased gut permeability and inhibited deglycosylation of ginsenoside Rb1 by intestinal microflora.

Footnotes

    • Received April 18, 2015.
    • Accepted August 10, 2015.
  • This research was supported by the National Youth Science Foundation of China [Grant 81102503], the Fundamental Research Funds for the Central Universities [Grant JKY2011018], and the National Science Foundation of China [Grant 81273587].

  • dx.doi.org/10.1124/dmd.115.064881.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (11)
Drug Metabolism and Disposition
Vol. 43, Issue 11
1 Nov 2015
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Research ArticleArticle

Alterations of Rb1 Pharmacokinetics in Diabetic Rats

Can Liu, Mengyue Hu, Haifang Guo, Mian Zhang, Ji Zhang, Feng Li, Zeyu Zhong, Yang Chen, Ying Li, Ping Xu, Jia Li, Li Liu and Xiaodong Liu
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1702-1710; DOI: https://doi.org/10.1124/dmd.115.064881

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Research ArticleArticle

Alterations of Rb1 Pharmacokinetics in Diabetic Rats

Can Liu, Mengyue Hu, Haifang Guo, Mian Zhang, Ji Zhang, Feng Li, Zeyu Zhong, Yang Chen, Ying Li, Ping Xu, Jia Li, Li Liu and Xiaodong Liu
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1702-1710; DOI: https://doi.org/10.1124/dmd.115.064881
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