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Research ArticleArticle

Involvement of Intestinal Uptake Transporters in the Absorption of Azithromycin and Clarithromycin in the Rat

Eric Garver, Erin D. Hugger, Shawn P. Shearn, Anuradha Rao, Paul A. Dawson, Charles B. Davis and Chao Han
Drug Metabolism and Disposition December 2008, 36 (12) 2492-2498; DOI: https://doi.org/10.1124/dmd.108.022285
Eric Garver
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Erin D. Hugger
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Shawn P. Shearn
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Anuradha Rao
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Paul A. Dawson
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Charles B. Davis
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Chao Han
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Abstract

Macrolide antibiotics azithromycin (AZI) and clarithromycin (CLARI) are large molecular weight compounds and are substrates for apically polarized efflux transporters such as P-glycoprotein, which can potentially restrict intestinal absorption. However, despite these undesired physicochemical and biopharmaceutical properties, AZI and CLARI exhibit moderate to excellent p.o. bioavailability in preclinical species and humans. Intestinal uptake transporters, such as organic anion transporting polypeptides (OATPs), can facilitate the uptake of drugs that are substrates and hence increase p.o. absorption. The present study was designed to determine whether the intestinal Oatps are involved in absorption of these macrolides. AZI or CLARI was dosed p.o. to Sprague-Dawley rats after p.o. administration with vehicle or rifamycin SV (RIF), an OATP inhibitor. The p.o. exposures of AZI and CLARI were reduced 65 and 45%, respectively, when coadministered with an optimized RIF regimen. The p.o. RIF had no affect on the total blood clearance of these macrolides and most likely did not cause induction of metabolizing enzymes and/or transporters. Therefore, the results suggest that inhibition of an RIF-sensitive uptake transporter such as Oatp along the rat gastrointestinal tract was responsible for reduced p.o. exposure of AZI and CLARI. In addition, AZI and CLARI caused inhibition of taurocholate uptake in rat Oatp1a5-transfected Madin-Darby canine kidney cell monolayers. The in vitro and in vivo results suggest that the intestinal Oatps are involved in the p.o. absorption of AZI and CLARI in the rat.

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

  • doi:10.1124/dmd.108.022285.

  • ABBREVIATIONS: AZI, azithromycin; CLARI, clarithromycin; P-gp, P-glycoprotein; OATP (human) or Oatp (rodent), organic anion transporting polypeptide; RIF, rifamycin SV; AUC, area under the blood-concentration time curve; GF120918, N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide; MDCK, Madin-Darby canine kidney; PBS, phosphate-buffered saline; DMSO, dimethyl sulfoxide; LC/MS/MS, liquid chromatography/tandem mass spectrometry; CLb, blood clearance; DNAUC, dose-normalized area under the blood-concentration time curve; ANOVA, analysis of variance.

    • Received June 3, 2008.
    • Accepted August 27, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (12)
Drug Metabolism and Disposition
Vol. 36, Issue 12
1 Dec 2008
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Research ArticleArticle

Involvement of Intestinal Uptake Transporters in the Absorption of Azithromycin and Clarithromycin in the Rat

Eric Garver, Erin D. Hugger, Shawn P. Shearn, Anuradha Rao, Paul A. Dawson, Charles B. Davis and Chao Han
Drug Metabolism and Disposition December 1, 2008, 36 (12) 2492-2498; DOI: https://doi.org/10.1124/dmd.108.022285

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Research ArticleArticle

Involvement of Intestinal Uptake Transporters in the Absorption of Azithromycin and Clarithromycin in the Rat

Eric Garver, Erin D. Hugger, Shawn P. Shearn, Anuradha Rao, Paul A. Dawson, Charles B. Davis and Chao Han
Drug Metabolism and Disposition December 1, 2008, 36 (12) 2492-2498; DOI: https://doi.org/10.1124/dmd.108.022285
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