title: Quantitative assessment of intestinal first-pass metabolism of oral drugs using portal-vein cannulated rats.
abstract: OBJECTIVE
  To evaluate the impact of intestinal first-pass metabolism (Fg) by cytochrome P4503A (CYP3A) and uridine 5'-diphosphate-glucuronosyltransferases (UGT) on in vivo oral absorption of their substrate drugs.
  
  
  METHODS
  CYP3A and UGT substrates were orally administered to portal-vein cannulated (PV) rats to evaluate their intestinal availability (Fa · Fg). In the case of CYP3A substrates, vehicle or 1-aminobenzotriazole (ABT), a potent inhibitor of CYP enzymes, was pretreated to assess Fg separately from Fa (Enzyme-inhibition method). On the other hand, since potent inhibitors of UGT have not been identified, Fg of UGT substrate was calculated from total amount of metabolites generated in enterocytes (Metabolite-distribution method).
  
  
  RESULTS
  After oral administration of CYP3A substrates in ABT-pretreated rats, the portal and systemic plasma concentrations of the metabolite were nearly the same, indicating almost complete inhibition of intestinal CYP3A-mediated metabolism. Using Enzyme-inhibition method, Fg of midazolam (1 mg/kg) was calculated as 0.71. Additionally, total amount of raloxifene-6-glucuronide generated in enterocytes after oral administration of raloxifene was estimated using Metabolite-distribution method and Fg of raloxifene (0.98 μmol/kg) was calculated as 0.21.
  
  
  CONCLUSIONS
  PV rats enabled in vivo quantitative assessment of intestinal first-pass metabolism by CYP3A and UGT. This method is useful for clarifying the cause of low bioavailability.
authors.affiliation: Pharmacokinetics and Safety Research Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd, 14 Shinomiya Minamigawara-cho, Yamashina-ku, Kyoto, 607-8042, Japan, matsuda_yoshiki@kaken.co.jp.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Matsuda
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Konno
authors.forename: Takashi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Mika
authors.initials: M
authors.lastname: Nagai
authors.forename: Takayuki
authors.initials: T
authors.lastname: Taguchi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Satsukawa
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamashita
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002404:Catheterization / Q000379:methods; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008297:Male; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000378:metabolism*; D011169:Portal Vein / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity / Q000187:drug effects / Q000502:physiology
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A