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.
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.