Identification of a Novel Route of Extraction of Sirolimus in Human Small Intestine: Roles of Metabolism and Secretion

Using Caco-2 cell monolayers expressing CYP3A4, we investigated the interplay between metabolism and transport on the first-pass intestinal extraction of the immunosuppressant sirolimus, a CYP3A4/P-glycoprotein substrate

Mary F. Paine; Louis Y. Leung; H. K. Lim; Kecheng Liao; Aram Oganesian; Mei-Yi Zhang; Kenneth E. Thummel; Paul B. Watkins

2003

Scholarcy highlights

  • Using Caco-2 cell monolayers expressing CYP3A4, we investigated the interplay between metabolism and transport on the first-pass intestinal extraction of the immunosuppressant sirolimus, a CYP3A4/P-glycoprotein substrate
  • Modified Caco-2 cells metabolizedsirolimus to the predicted amounts of CYP3A4-mediated products based on CYP3A4 content, which was ∼20% of that measured in human small intestinal mucosal homogenate.Sirolimus degraded to the known ring-opened product, seco-rapamycin
  • M2 was formed from purified seco-rapamycin in the homogenates, it was not detected in cells when seco-rapamycin was added to the apical compartment, because seco-rapamycin was essentially impermeable to the apical membrane
  • Seco-rapamycin, and M2 were all actively secreted across the apical membrane, and secretion of each was inhibited by the P-gp inhibitor LY335979
  • Along with CYP3A4-mediated metabolism and P-gp-mediated secretion, we conclude that the following novel pathway, which occurs at least in the intestine, may contribute significantly to the first-pass extraction of sirolimus in humans: intracellular degradation of sirolimus to seco-rapamycin, metabolism of seco-rapamycin to M2 by an unidentified nonmicrosomal enzyme, and P-gp-mediated secretion of M2 and seco-rapamycin
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