Investigating the barriers to bioavailability of macrolide antibiotics in the rat

  • Jasna Padovan
  • Jovica Ralić
  • Vatroslav Letfus
  • Astrid Milić
  • Vlatka Bencetić Mihaljević
Original Paper

Abstract

The aim of this study was to compare the roles of gastrointestinal absorption and hepatic extraction as barriers to oral bioavailability for macrolide antibiotics erythromycin, clarithromycin, roxithromycin and telithromycin. In this study, the in vitro metabolic stability in rat liver microsomes and hepatocytes, as well as the in vivo pharmacokinetics in rats were determined following intravenous, intraportal, oral and intraduodenal routes of administration. Pharmacokinetic parameters were calculated for each compound for each route of administration. In vitro metabolic stability studies point to low intrinsic clearance of the tested macrolides in both microsomes (<1 mL/min/g) and hepatocytes (<1 mL/min/g), indicating good stability. The oral bioavailability in rat was low to moderate (14, 36, 36 and 25% for erythromycin, clarithromycin, roxithromycin and telithromycin, respectively). Upon intraduodenal dosing, the bioavailability increased by 1.3–3-fold, the highest increase being with roxithromycin, suggesting some loss due to gastric instability. Following portal vein administration, no hepatic first pass effect was observed with roxithromycin, less than 10% with telithromycin, and ca. 20 and 25% for clarithromycin and erythromycin. Our data showed that the tested macrolides display good in vitro metabolic stability, as was confirmed in vivo where a low hepatic first pass effect was observed. The limited oral bioavailability is likely due to poor oral absorption and/or intestinal first pass metabolism.

Keywords

Macrolide antibiotics Rat Pharmacokinetics Barriers Bioavailability 

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Copyright information

© Springer-Verlag France 2011

Authors and Affiliations

  • Jasna Padovan
    • 1
    • 2
  • Jovica Ralić
    • 1
    • 2
  • Vatroslav Letfus
    • 1
    • 2
  • Astrid Milić
    • 1
    • 2
  • Vlatka Bencetić Mihaljević
    • 1
    • 2
  1. 1.GlaxoSmithKline Research Centre Zagreb LtdZagrebCroatia
  2. 2.Galapagos Research Center Ltd.ZagrebCroatia

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