Disposition of orally administered a promising chemotherapeutic agent flavopiridol in the intestine.
Drug Dev Ind Pharm
; 39(6): 845-53, 2013 Jun.
Article
em En
| MEDLINE
| ID: mdl-22563974
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 T1/2 (> 260 min), and short peak time (<20 min). In the Caco-2 cell culture model, the bidirectional permeability of FLAP was 0.47 × 10(-5) cm/s to 1.53 × 10(-5) 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Piperidinas
/
Flavonoides
/
Absorção Intestinal
/
Antineoplásicos
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article