Metabolism, oral bioavailability and pharmacokinetics of chemopreventive kaempferol in rats.

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  • Author(s): Barve A;Barve A; Chen C; Hebbar V; Desiderio J; Saw CL; Kong AN
  • Source:
    Biopharmaceutics & drug disposition [Biopharm Drug Dispos] 2009 Oct; Vol. 30 (7), pp. 356-65.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Wiley Country of Publication: England NLM ID: 7911226 Publication Model: Print Cited Medium: Internet ISSN: 1099-081X (Electronic) Linking ISSN: 01422782 NLM ISO Abbreviation: Biopharm Drug Dispos Subsets: MEDLINE
    • Publication Information:
      Publication: Chichester : Wiley
      Original Publication: Chichester [Eng.] Wiley.
    • Subject Terms:
      Biological Availability* ; Dose-Response Relationship, Drug*; Antineoplastic Agents/*pharmacokinetics ; Kaempferols/*pharmacokinetics ; Tissue Distribution/*drug effects; Animals ; Antineoplastic Agents/pharmacology ; HIV Protease Inhibitors/pharmacokinetics ; HIV Protease Inhibitors/pharmacology ; Humans ; Kaempferols/metabolism ; Kaempferols/pharmacology ; Male ; Rats ; Rats, Sprague-Dawley
    • Abstract:
      The purpose of this study was to compare the hepatic and small intestinal metabolism, and to examine bioavailability and gastro-intestinal first-pass effects, of kaempferol in rats. Liver and small intestinal microsomes fortified with either NADPH or UDPGA were incubated with varying concentrations of kaempferol for up to 120 min. Based on the values of the kinetic constants (K(m) and V(max)), the propensity for UDPGA-dependent conjugation compared with NADPH-dependent oxidative metabolism was higher for both hepatic and small intestinal microsomes. Male Sprague-Dawley rats were administered kaempferol intravenously (i.v.) (10, 25 mg/kg) or orally (100, 250 mg/kg). Gastro-intestinal first-pass effects were observed by collecting portal blood after oral administration of 100 mg/kg kaempferol. Pharmacokinetic parameters were obtained by non-compartmental analysis using WinNonlin. After i.v. administration, the plasma concentration-time profiles for 10 and 25 mg/kg were consistent with high clearance (approximately 3 L/hr/kg) and large volumes of distribution (8-12 L/hr/kg). The disposition was characterized by a terminal half-life value of 3-4 h. After oral administration the plasma concentration-time profiles demonstrated fairly rapid absorption (t(max) approximately 1-2 h). The area under the curve (AUC) values after i.v. and oral doses increased approximately proportional to the dose. The bioavailability (F) was poor at approximately 2%. Analysis of portal plasma after oral administration revealed low to moderate absorption. Taken together, the low F of kaempferol is attributed in part to extensive first-pass metabolism by glucuronidation and other metabolic pathways in the gut and in the liver.
      (2009 John Wiley & Sons, Ltd.)
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    • Grant Information:
      R01 CA152826 United States CA NCI NIH HHS; P30 ES005022 United States ES NIEHS NIH HHS; R01 CA118947 United States CA NCI NIH HHS; R01 CA118947-04 United States CA NCI NIH HHS; R01-CA118947 United States CA NCI NIH HHS
    • Accession Number:
      0 (Antineoplastic Agents)
      0 (HIV Protease Inhibitors)
      0 (Kaempferols)
      731P2LE49E (kaempferol)
    • Publication Date:
      Date Created: 20090902 Date Completed: 20100115 Latest Revision: 20211020
    • Publication Date:
      20231215
    • Accession Number:
      PMC3580176
    • Accession Number:
      10.1002/bdd.677
    • Accession Number:
      19722166