PMID: 15385826Sep 24, 2004Paper

New insights into drug absorption: studies with sirolimus

Therapeutic Drug Monitoring
Mary F PainePaul B Watkins

Abstract

Sirolimus is a recently marketed immunosuppressant that, in common with cyclosporine and tacrolimus, exhibits a low average oral bioavailability (approximately 20%). Likewise, sirolimus is a substrate for the major drug-metabolizing enzyme cytochrome P450 3A4 (CYP3A4) and the efflux transporter P-glycoprotein (P-gp), both of which are expressed in close proximity in epithelial cells lining the small intestine. Using CYP3A4-expressing Caco-2 cell monolayers, we examined the interplay between metabolism and transport on the intestinal first-pass extraction of sirolimus. Modified Caco-2 cells metabolized [14C]sirolimus to the same CYP3A4-mediated metabolites as human small intestinal and liver microsomes. [14C]Sirolimus also degraded to the known ring-opened product, seco-sirolimus. A ring-opened dihydro species (M2) was, surprisingly, the major product detected in cells at all sirolimus concentrations examined (2-100 micromol/L) and in incubations with human liver and intestinal homogenates but not in corresponding microsomes. M2 formation was NADPH-dependent but unaffected by prototypical CYP3A4 inhibitors. Although M2 was formed from purified seco-sirolimus (20 micromol/L) in the homogenates, it was not detected in cells when s...Continue Reading

References

Apr 1, 1997·Clinical Pharmacology and Therapeutics·G M FerronW J Jusko
Jun 6, 2000·Advanced Drug Delivery Reviews·D D ShenK E Thummel
Sep 25, 2001·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·A Ayrton, P Morgan
Sep 29, 2001·Advanced Drug Delivery Reviews·L Z Benet, C L Cummins
Mar 22, 2002·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

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Citations

Apr 25, 2008·Expert Opinion on Drug Metabolism & Toxicology·Huadong SunK Sandy Pang
Mar 31, 2012·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Jason A SprowlAlex Sparreboom
Apr 21, 2009·Pharmacology & Therapeutics·Gopala K RanganKok On Ho
Jan 19, 2006·Therapeutic Drug Monitoring·Louis Y LeungJames J Zimmerman
May 21, 2005·Therapeutic Drug Monitoring·Ian S WestleyMaree J James
Jul 20, 2017·Transplant Infectious Disease : an Official Journal of the Transplantation Society·Andreas H GrollRoger J M Brüggemann

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