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New insights into drug absorption: studies with sirolimus.
- Source :
-
Therapeutic drug monitoring [Ther Drug Monit] 2004 Oct; Vol. 26 (5), pp. 463-7. - Publication Year :
- 2004
-
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 seco-sirolimus was added to the apical compartment because seco-sirolimus was essentially impermeable to the apical membrane. Sirolimus, seco-sirolimus (basolaterally dosed), and M2 were all secreted across the apical membrane, and secretion of each was inhibited by the P-gp inhibitor LY335979 (zosuquidar trihydrochloride). Along with CYP3A4-mediated metabolism and P-gp-mediated efflux, a novel elimination pathway was identified that may also contribute to the first-pass extraction, and hence low oral bioavailability, of sirolimus. This new insight into the intestinal elimination of sirolimus, which was not identified using traditional drug metabolism/transport screening methods, may represent another source for the limited absorption of sirolimus.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
Biological Transport
Caco-2 Cells
Carbon Radioisotopes
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System metabolism
Dibenzocycloheptenes pharmacology
Dose-Response Relationship, Drug
Humans
Immunosuppressive Agents pharmacokinetics
Intestinal Absorption
Permeability
Quinolines pharmacology
Sirolimus pharmacokinetics
Vitamin D pharmacology
Immunosuppressive Agents metabolism
Sirolimus metabolism
Vitamin D analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 0163-4356
- Volume :
- 26
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Therapeutic drug monitoring
- Publication Type :
- Academic Journal
- Accession number :
- 15385826
- Full Text :
- https://doi.org/10.1097/00007691-200410000-00001