PMID: 11907172Mar 22, 2002Paper

Identification of a novel route of extraction of sirolimus in human small intestine: roles of metabolism and secretion

The Journal of Pharmacology and Experimental Therapeutics
Mary F PainePaul B Watkins

Abstract

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 (P-gp) substrate. Modified Caco-2 cells metabolized [(14)C]sirolimus to the predicted amounts of CYP3A4-mediated products based on CYP3A4 content, which was approximately 20% of that measured in human small intestinal mucosal homogenate. [(14)C]Sirolimus also degraded to the known ring-opened product, seco-rapamycin. Unexpectedly, a ring-opened dihydro metabolite (M2) was the major product detected in cells at all sirolimus concentrations examined (2-100 microM). Greater M2 formation after apical versus basolateral dosing (1.6-fold) was explained by higher intracellular content of sirolimus after apical dosing. M2 was not detected in incubations with human liver and intestinal microsomes but was readily detected with corresponding homogenates. M2 formation was NADPH-dependent but unaffected by the CYP3A4 inhibitors ketoconazole and troleandomycin. Although M2 was formed from purified seco-rapamycin (20 microM) in the homogenates, it was not detected in cells when seco-rapamycin was added to the apical compartment, becaus...Continue Reading

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Citations

Mar 3, 2007·Pharmaceutical Research·Lilian G YengiJohn Kao
Oct 25, 2003·American Journal of Pharmacogenomics : Genomics-related Research in Drug Development and Clinical Practice·Salim FredericksIain A M MacPhee
Apr 25, 2008·Expert Opinion on Drug Metabolism & Toxicology·Huadong SunK Sandy Pang
Jan 13, 2005·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·Titte R SrinivasBruce Kaplan
Apr 26, 2006·Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation·Francisco M MartyJoseph H Antin
Sep 24, 2004·Therapeutic Drug Monitoring·Mary F PainePaul B Watkins
Jan 19, 2006·Therapeutic Drug Monitoring·Louis Y LeungJames J Zimmerman
Oct 16, 2004·The Journal of Pharmacology and Experimental Therapeutics·Mary F PainePaul B Watkins
Oct 22, 2003·The Journal of Pharmacology and Experimental Therapeutics·Carolyn L CumminsLeslie Z Benet
Jan 14, 2004·The Journal of Pharmacology and Experimental Therapeutics·Stéphane J MoulyPaul B Watkins
Dec 21, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mary F PainePaul B Watkins
Nov 20, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·K Sandy Pang
Aug 9, 2019·Molecular Pharmaceutics·Aze WilsonRichard B Kim

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