title: Disposition of orally administered a promising chemotherapeutic agent flavopiridol in the intestine.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Bijun
authors.initials: B
authors.lastname: Xia
authors.forename: Xi
authors.initials: X
authors.lastname: Liu
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhou
authors.forename: Qian
authors.initials: Q
authors.lastname: Feng
authors.forename: Ye
authors.initials: Y
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Zhongqiu
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism*; D001682:Biological Availability; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D018938:Caco-2 Cells; D005419:Flavonoids / Q000008:administration & dosage* / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008297:Male; D009924:Organ Culture Techniques; D010880:Piperidines / Q000008:administration & dosage* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib