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Disposition of orally administered a promising chemotherapeutic agent flavopiridol in the intestine.
- Source :
- Drug Development & Industrial Pharmacy; Jun2013, Vol. 39 Issue 6, p845-853, 9p, 1 Chart, 7 Graphs
- Publication Year :
- 2013
-
Abstract
- Background: Flavopiridol (FLAP) is a promising chemotherapeutic agent undergoing clinical phase I and phase II trials, and a number of studies have elucidated its hepatic metabolism and biliary disposition. Methods: In present study, the intestinal disposition of orally administered FLAP was characterized through pharmacokinetic studies in rats as well as absorption and metabolism studies using a Caco-2 cell culture and four-site perfused rat intestinal models. Results: Pharmacokinetic results show that FLAP has high bioavailability (> 75%), long T<subscript>1/2</subscript> (> 260 min), and short peak time (<20 min). In the Caco-2 cell culture model, the bidirectional permeability of FLAP was 0.47 × 10<superscript>−5</superscript> cm/s to 1.53 × 10<superscript>−5</superscript> cm/s and the efflux ratios were 3.27 and 2.17 at 10 and 30 μM, respectively. Apical loading of two P-glycoprotein (P-gp) inhibitors, cyclosporine A and verapamil, significantly increased the intracellular amount of FLAP and lowered its efflux ratio. In the four-site model, 10 and 40 μM FLAP perfusions were well absorbed at various regions of the intestine, and the biliary excretions of FLAP glucuronides were 1.60-2.84 nmol and 12.47-17.33 nmol, respectively. Conclusion: FLAP possesses high oral bioavailability and good absorption in the intestine, in which FLAP may be subjected to a P-gp efflux. Biliary excretion is the main elimination pathway for FLAP glucuronide and its enterohepatic cycling could be indicated. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 03639045
- Volume :
- 39
- Issue :
- 6
- Database :
- Complementary Index
- Journal :
- Drug Development & Industrial Pharmacy
- Publication Type :
- Academic Journal
- Accession number :
- 87372161
- Full Text :
- https://doi.org/10.3109/03639045.2012.682224