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Research ArticleArticle

Involvement of Organic Anion-Transporting Polypeptides in the Hepatic Uptake of Dioscin in Rats and Humans

Aijie Zhang, Changyuan Wang, Qi Liu, Qiang Meng, Jinyong Peng, Huijun Sun, Xiaochi Ma, Xiaokui Huo and Kexin Liu
Drug Metabolism and Disposition May 2013, 41 (5) 994-1003; DOI: https://doi.org/10.1124/dmd.112.049452
Aijie Zhang
Department of Clinical Pharmacology, College of Pharmacy (A.Z., C.W., Q.L., Q.M., J.P., H.S., X.M., X.H., K.L.), Provincial Key Laboratory for Pharmacokinetics and Transport (C.W., Q.L., Q.M., J.P., H.S., X.M., K.L.), and Research Institute of Integrated Traditional and Western Medicine, Dalian Medical University, Liaoning, China (J.P., X.M., K.L.)
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Changyuan Wang
Department of Clinical Pharmacology, College of Pharmacy (A.Z., C.W., Q.L., Q.M., J.P., H.S., X.M., X.H., K.L.), Provincial Key Laboratory for Pharmacokinetics and Transport (C.W., Q.L., Q.M., J.P., H.S., X.M., K.L.), and Research Institute of Integrated Traditional and Western Medicine, Dalian Medical University, Liaoning, China (J.P., X.M., K.L.)
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Qi Liu
Department of Clinical Pharmacology, College of Pharmacy (A.Z., C.W., Q.L., Q.M., J.P., H.S., X.M., X.H., K.L.), Provincial Key Laboratory for Pharmacokinetics and Transport (C.W., Q.L., Q.M., J.P., H.S., X.M., K.L.), and Research Institute of Integrated Traditional and Western Medicine, Dalian Medical University, Liaoning, China (J.P., X.M., K.L.)
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Qiang Meng
Department of Clinical Pharmacology, College of Pharmacy (A.Z., C.W., Q.L., Q.M., J.P., H.S., X.M., X.H., K.L.), Provincial Key Laboratory for Pharmacokinetics and Transport (C.W., Q.L., Q.M., J.P., H.S., X.M., K.L.), and Research Institute of Integrated Traditional and Western Medicine, Dalian Medical University, Liaoning, China (J.P., X.M., K.L.)
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Jinyong Peng
Department of Clinical Pharmacology, College of Pharmacy (A.Z., C.W., Q.L., Q.M., J.P., H.S., X.M., X.H., K.L.), Provincial Key Laboratory for Pharmacokinetics and Transport (C.W., Q.L., Q.M., J.P., H.S., X.M., K.L.), and Research Institute of Integrated Traditional and Western Medicine, Dalian Medical University, Liaoning, China (J.P., X.M., K.L.)
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Huijun Sun
Department of Clinical Pharmacology, College of Pharmacy (A.Z., C.W., Q.L., Q.M., J.P., H.S., X.M., X.H., K.L.), Provincial Key Laboratory for Pharmacokinetics and Transport (C.W., Q.L., Q.M., J.P., H.S., X.M., K.L.), and Research Institute of Integrated Traditional and Western Medicine, Dalian Medical University, Liaoning, China (J.P., X.M., K.L.)
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Xiaochi Ma
Department of Clinical Pharmacology, College of Pharmacy (A.Z., C.W., Q.L., Q.M., J.P., H.S., X.M., X.H., K.L.), Provincial Key Laboratory for Pharmacokinetics and Transport (C.W., Q.L., Q.M., J.P., H.S., X.M., K.L.), and Research Institute of Integrated Traditional and Western Medicine, Dalian Medical University, Liaoning, China (J.P., X.M., K.L.)
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Xiaokui Huo
Department of Clinical Pharmacology, College of Pharmacy (A.Z., C.W., Q.L., Q.M., J.P., H.S., X.M., X.H., K.L.), Provincial Key Laboratory for Pharmacokinetics and Transport (C.W., Q.L., Q.M., J.P., H.S., X.M., K.L.), and Research Institute of Integrated Traditional and Western Medicine, Dalian Medical University, Liaoning, China (J.P., X.M., K.L.)
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Kexin Liu
Department of Clinical Pharmacology, College of Pharmacy (A.Z., C.W., Q.L., Q.M., J.P., H.S., X.M., X.H., K.L.), Provincial Key Laboratory for Pharmacokinetics and Transport (C.W., Q.L., Q.M., J.P., H.S., X.M., K.L.), and Research Institute of Integrated Traditional and Western Medicine, Dalian Medical University, Liaoning, China (J.P., X.M., K.L.)
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Abstract

The objective of this study was to clarify the mechanism underlying hepatic uptake of dioscin (diosgenyl 2,4-di-O-a-L-rhamnopyranosyl-p-D-glucopyranoside), an herbal ingredient with antihepatitis activity, in rats and humans. The liver uptake index (LUI) in vivo, perfused rat liver in situ, rat liver slices, isolated rat hepatocytes, and human organic anion-transporting polypeptide (OATP)–transfected cells in vitro were used to evaluate hepatic uptake of dioscin. Values of 11.9% ± 1.6% and 15.0% ± 0.9% of dose for uptake of dioscin were observed by LUI in vivo and perfused rat livers in situ, respectively. The time course of dioscin uptake by rat liver slices was temperature-dependent. Uptake of dioscin by rat liver slices and isolated rat hepatocytes was inhibited significantly by Oatp modulators, such as ibuprofen (Oatp1a1 inhibitor), digoxin (Oatp1a4 substrate), and glycyrrhizic acid (Oatp1b2 inhibitor), but not by TEA or p-aminohippurate. Uptake of dioscin in rat hepatocytes and OATP1B3-human embryonic kidney (HEK) 293 cells indicated a saturable process with a Km of 3.75 ± 0.51 μM and 2.08 ± 0.27 μM, respectively. (–)-Epigallocatechin gallate, cyclosporin A, rifampicin, and telmisartan inhibited transport of dioscin in OATP1B3-HEK293 cells. However, transcellular transport of dioscin in OATP1B1- or OATP1B1/multidrug resistance-associated protein 2–Madin-Darby canine kidney strain II cells was not observed. These results indicate that hepatic uptake of dioscin is involved in OATP1B3 in humans, and multiple Oatps might participate in this process in rats.

Footnotes

    • Received October 5, 2012.
    • Accepted February 8, 2013.
  • This work was supported in part by a grant from the National Natural Science Foundation of China [Grants 81072694 and 81273580]; and a grant from the Dalian government [Grant 2010E12SF060].

  • dx.doi.org/10.1124/dmd.112.049452.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (5)
Drug Metabolism and Disposition
Vol. 41, Issue 5
1 May 2013
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Research ArticleArticle

Hepatic Uptake of Dioscin via OATPs in Rats and Humans

Aijie Zhang, Changyuan Wang, Qi Liu, Qiang Meng, Jinyong Peng, Huijun Sun, Xiaochi Ma, Xiaokui Huo and Kexin Liu
Drug Metabolism and Disposition May 1, 2013, 41 (5) 994-1003; DOI: https://doi.org/10.1124/dmd.112.049452

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Research ArticleArticle

Hepatic Uptake of Dioscin via OATPs in Rats and Humans

Aijie Zhang, Changyuan Wang, Qi Liu, Qiang Meng, Jinyong Peng, Huijun Sun, Xiaochi Ma, Xiaokui Huo and Kexin Liu
Drug Metabolism and Disposition May 1, 2013, 41 (5) 994-1003; DOI: https://doi.org/10.1124/dmd.112.049452
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