Species difference in intestinal absorption mechanism of etoposide and digoxin between cynomolgus monkey and rat

IR

Search this article

Abstract

金沢大学医薬保健研究域薬学系 金沢大学医薬保健研究域医学系

Purpose. The oral bioavailability of some therapeutic agents is markedly lower in cynomolgus monkeys than in humans. We investigated small-intestinal absorption of the P-glycoprotein (P-gp) substrates etoposide and digoxin in monkeys to clarify the influence of efflux transport on their intestinal permeability. Methods. The pharmacokinetics of etoposide and digoxin was examined in monkeys and rats after oral and intravenous administration. Intestinal permeability and segmental differences in permeability were investigated with an Ussing-type chamber. Results. The bioavailability of etoposide was 12.9 and 13.9% in monkeys and rats, respectively. Total body clearance of etoposide in monkeys was much less than hepatic blood flow, suggesting that the bioavailability would be limited at intestinal absorption. Marked vectorial transport of etoposide in the secretory direction was observed in rats, especially in the lower small intestine, and segmental differences were consistent with the distribution of P-gp expression. Vectorial transport was minimal in monkey small intestine. Our kinetic analysis indicated that P-gp contributes little to the intestinal permeability of etoposide and digoxin in monkeys, and apical uptake is rate-limiting. Conclusion. Low bioavailability of etoposide in monkeys is due to poor intestinal uptake resulting from low influx from the apical side, rather than secretion via P-gp. © 2008 Springer Science+Business Media, LLC.

Journal

  • Pharmaceutical Research

    Pharmaceutical Research 25 (11), 2467-2476, 2008-11-01

    Springer Science+Business Media B.V.

Related Projects

See more

Details 詳細情報について

  • CRID
    1050845760880894464
  • NII Article ID
    120000997157
  • NII Book ID
    AA10632083
  • ISSN
    07248741
  • Web Site
    http://hdl.handle.net/2297/12346
  • Text Lang
    en
  • Article Type
    journal article
  • Data Source
    • IRDB
    • CiNii Articles
    • KAKEN

Report a problem

Back to top