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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Human Organic Anion Transporting Polypeptide-C (SLC21A6) Is a Major Determinant of Rifampin-Mediated Pregnane X Receptor Activation

Rommel G. Tirona, Brenda F. Leake, Allan W. Wolkoff and Richard B. Kim
Journal of Pharmacology and Experimental Therapeutics January 2003, 304 (1) 223-228; DOI: https://doi.org/10.1124/jpet.102.043026
Rommel G. Tirona
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Brenda F. Leake
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Allan W. Wolkoff
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Richard B. Kim
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Abstract

Rifampin, a member of the rifamycin class of antibiotics, is well known for its ability to induce drug-metabolizing enzymes and transporters, through activation of the pregnane X receptor. Available data suggest rifampin entry into hepatocytes may be transporter-mediated. Accordingly, it is therefore plausible that modulation of the achievable intracellular concentration of rifampin by drug uptake transporters would influence the degree of induction. In this study, we expressed an array of known hepatic uptake transporters to show the key hepatic rifampin uptake transporters are liver-specific members of the organic anion transporting polypeptide family (OATP). Indeed, both OATP-C and OATP8 seemed capable of mediating rifampin uptake into HeLa cells. OATP-C, however, seemed to have far greater affinity and capacity for rifampin transport. In addition, several allelic variants of OATP-C known to be present among European and African Americans were found to have markedly decreased rifampin transport activity. In cell-based, transactivation assays, OATP-C expression was associated with increased cellular rifampin retention as well as potentiation of PXR reporter gene activity. This is the first demonstration of an uptake transporter such as OATP-C, in modulating PXR function, and sheds important new insight into our understanding of the molecular determinants of PXR-mediated inductive processes.

Footnotes

  • This work was supported in part by U.S. Public Health Service Grants GM31304 (to R.B.K.), GM54724 (to R.B.K.), and DK23026 and DK41296 (to A.W.W.).

  • DOI: 10.1124/jpet.102.043026

  • Abbreviations:
    P450
    cytochrome P450
    PXR
    pregnane X receptor
    BSP
    bromosulfophthalein
    OATP
    organic anion transporting polypeptide
    OAT
    organic anion transporter
    OCT
    organic cation transporter
    NTCP
    sodium-dependent taurocholate transporting polypeptide
    E2G
    estradiol-17β-glucuronide
    CyA
    cyclosporin A
    • Received August 9, 2002.
    • Accepted September 13, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 304 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 304, Issue 1
1 Jan 2003
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Human Organic Anion Transporting Polypeptide-C (SLC21A6) Is a Major Determinant of Rifampin-Mediated Pregnane X Receptor Activation

Rommel G. Tirona, Brenda F. Leake, Allan W. Wolkoff and Richard B. Kim
Journal of Pharmacology and Experimental Therapeutics January 1, 2003, 304 (1) 223-228; DOI: https://doi.org/10.1124/jpet.102.043026

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Human Organic Anion Transporting Polypeptide-C (SLC21A6) Is a Major Determinant of Rifampin-Mediated Pregnane X Receptor Activation

Rommel G. Tirona, Brenda F. Leake, Allan W. Wolkoff and Richard B. Kim
Journal of Pharmacology and Experimental Therapeutics January 1, 2003, 304 (1) 223-228; DOI: https://doi.org/10.1124/jpet.102.043026
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