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Research ArticleArticle

Clarithromycin Is Absorbed by an Intestinal Uptake Mechanism That Is Sensitive to Major Inhibition by Rifampicin: Results of a Short-Term Drug Interaction Study in Foals

Jette Peters, Karen Eggers, Stefan Oswald, Wiebke Block, Dieter Lütjohann, Marc Lämmer, Monica Venner and Werner Siegmund
Drug Metabolism and Disposition March 2012, 40 (3) 522-528; DOI: https://doi.org/10.1124/dmd.111.042267
Jette Peters
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Karen Eggers
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Stefan Oswald
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Wiebke Block
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Dieter Lütjohann
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Marc Lämmer
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Monica Venner
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Werner Siegmund
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Abstract

Pulmonary penetration of clarithromycin (CLR) in epithelial lining fluid (ELF) and bronchoalveolar lavage cells (BALCs) can be influenced by CYP3A4, by P-glycoprotein, and, according to our hypothesis, by a member of the organic anion-transporting protein (OATP) family, for which rifampicin (RIF) is inhibiting in single doses but inducing after long-term coadministration. To assess the partial inhibitory effect, we measured absorption and pulmonary distribution of CLR after short-term (2.5-day) coadministration of RIF, after which up-regulation is not expected. The drug interaction study was performed with five doses (12-h interval) of CLR (7.5 mg/kg) and RIF (10 mg/kg) in nine healthy foals; horse transporters are very similar in protein sequence and transcriptional regulation to the human analogs. RIF was equally distributed in ELF but reached half the plasma levels in BALCs. The deacetylated metabolite accumulated 1.4- to 6-fold in ELF and 8- to 60-fold in BALCs. CLR did not significantly influence the distribution of RIF. CLR and 14-hydroxyclarithromycin (14OH-CLR) accumulated approximately 20- to 40-fold and 1.5- to 4.5-fold in ELF and 300- to 1800-fold and 25- to 90-fold in BALCs, respectively. With RIF, plasma levels of CLR decreased by more than 70% without changes in 14OH-CLR formation, the half-lives of CLR and 14OH-CLR, and the 4β-hydroxycholesterol/cholesterol ratio (a surrogate for CYP3A4 induction). CLR was an inhibitor of OATP1B3 (IC50 = 9.50 ± 3.50 μM), OATP1B1 (IC50 = 46.0 ± 2.27 μM), OATP1A2 (IC50 = 92.6 ± 1.49 μM), and OATP2B1 (IC50 = 384 ± 5.30 μM) but was not a substrate for these transporters in transfected human embryonic kidney cells. In conclusion, despite having no significant inducing effects, RIF decreased plasma levels of CLR below the minimal inhibitory concentration required to inhibit 90% of growth of pathogenic bacteria, most likely through inhibition of an unknown intestinal uptake transporter.

Footnotes

  • The clinical part of the study was generously supported by the Paul-Schockmoehle Lewitz Stud (Neustadt-Glewe, Germany). The analytical and molecular and cell biological parts were supported by a grant from the German Federal Ministry for Education and Research [Grant 03IP612] (InnoProfile).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.111.042267.

  • ABBREVIATIONS:

    BEC
    bronchoepithelial cell
    ABCB1
    P-glycoprotein
    ABCC2
    multidrug resistance-related protein 2
    CLR
    clarithromycin
    BALC
    bronchoalveolar lavage cell
    OATP
    organic anion-transporting protein
    BSP
    bromosulfophthalein
    E3S
    estrone-3-sulfate
    ELF
    epithelial lining fluid
    PXR
    pregnane-X receptor
    RIF
    rifampicin
    14OH-CLR
    14-hydroxyclarithromycin
    DAc-RIF
    25-O-desacetylrifampicin
    4βOH-C
    4β-hydroxycholesterol
    MIC90
    minimal inhibitory concentration required to inhibit 90% of growth
    AUC
    area under the plasma concentration-time curve
    HEK
    human embryonic kidney.

  • Received August 8, 2011.
  • Accepted December 14, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (3)
Drug Metabolism and Disposition
Vol. 40, Issue 3
1 Mar 2012
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Research ArticleArticle

RIFAMPICIN-CLARITHROMYCIN DRUG INTERACTION IN FOALS

Jette Peters, Karen Eggers, Stefan Oswald, Wiebke Block, Dieter Lütjohann, Marc Lämmer, Monica Venner and Werner Siegmund
Drug Metabolism and Disposition March 1, 2012, 40 (3) 522-528; DOI: https://doi.org/10.1124/dmd.111.042267

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Research ArticleArticle

RIFAMPICIN-CLARITHROMYCIN DRUG INTERACTION IN FOALS

Jette Peters, Karen Eggers, Stefan Oswald, Wiebke Block, Dieter Lütjohann, Marc Lämmer, Monica Venner and Werner Siegmund
Drug Metabolism and Disposition March 1, 2012, 40 (3) 522-528; DOI: https://doi.org/10.1124/dmd.111.042267
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