title: In Situ intestinal perfusion of irinotecan: application to P-gp mediated drug interaction and introduction of an improved HPLC assay.
abstract: OBJECTIVE
  To determine experimentally the intestinal permeability of the anticancer prodrug irinotecan, and to quantify the amount of its cytotoxic metabolite SN-38 that is intestinally excreted (exsorped) as a predictor of intestinal toxicity, and to assess the effect of p-glycoprotein (p-gp) inhibitors (verapamil as a model) on the permeability and toxicity of irinotecan.
  
  
  METHODS
  Single pass intestinal perfusion of rat's whole length small intestines is applied to assess the permeability of the parent drug and quantify the intestinally excreted metabolite. The perfusion solution contained 30μg/ml of irinotecan (control group) without or with verapamil (verapamil group). A simple reversed phase HPLC method with UV detection is developed and validated for simultaneous determination of irinotecan and SN-38 using camptothecin as an internal standard.
  
  
  RESULTS
  HPLC-UV method found to be simple, specific, accurate, and precise. Effective permeability coefficient of irinotecan found to be 4.9±1.7 10-3 mm/min and was doubled in verapamil group (P=0.007). Average cumulative amount of SN-38 exsorped found to be 29 ng/cm over 2 hours perfusion time which was decreased to 15 ng/cm in verapamil group (P=0.016).
  
  
  CONCLUSIONS
  in situ intestinal perfusion method was successfully applied to quantify the permeability of irinotecan and the exsorption of SN-38 in the same experiment, in a manner that robustly reflects real in vivo situation. P-gp inhibition using verapamil found to significantly enhance the intestinal permeability of irinotecan and potentially decrease the intestinal toxicity due to SN-38 exposure.
authors: Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science andTechnology, Wuhan PR China.
authors: Abdullah Khalil
authors: AK
authors: Rabba
authors: Luqin
authors: L
authors: Si
authors: Kewen
authors: K
authors: Xue
authors: Ming
authors: M
authors: Li
authors: Gao
authors: G
authors: Li
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002138:Calibration; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004347:Drug Interactions; D004355:Drug Stability; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D000077146:Irinotecan; D008297:Male; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D059004:Topoisomerase I Inhibitors / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D014700:Verapamil; D002166:Camptothecin