title: Effects of myricetin on the bioavailability of carvedilol in rats.
abstract: BACKGROUND
  As an inhibitor of CYP2C9, CYP2D6 and P-gp, myricetin might affect the bioavailability of carvedilol when myricetin and carvedilol are used concomitantly for the prevention or therapy of cardiovascular diseases as a combination therapy. However, the effect of myricetin on the pharmacokinetics of carvedilol has not been reported in vivo.
  
  
  OBJECTIVE
  This study investigated the effects of myricetin on the pharmacokinetics of carvedilol after oral or intravenous administration of carvedilol in rats.
  
  
  METHODS
  Carvedilol was administered orally or intravenously with or without oral administration of myricetin to rats.
  
  
  RESULTS
  The effects of myricetin on P-gp, CYP2C9 and 2D6 activity were evaluated. Myricetin inhibited CYP2C9 and CYP2D6 enzyme activity with IC50 of 13 and 57 μM, respectively. In addition, myricetin significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group, the AUC was significantly increased by 52.0-85.1%, and the C(max) was significantly increased by 93.1-133.4% in the presence of myricetin after oral administration of carvedilol. Consequently, the relative bioavailability of carvedilol was increased by 1.17- to 1.85-fold and the absolute bioavailability of carvedilol in the presence of myricetin was increased by 18.1-86.4%. T(max) was significantly decreased.
  
  
  CONCLUSIONS
  The enhanced oral bioavailability of carvedilol may result from both inhibition of CYP2C9 or CYP2D6-mediated metabolism and P-gp-mediated efflux of carvedilol in small intestine and/or in liver by myricetin rather than reducing renal elimination. Concomitant use of myricetin or myricetin-containing dietary supplements with carvedilol will require close monitoring for potential drug interactions.
authors: College of Pharmacy, Chosun University, Gwangju, Republic of Korea.
authors: W
authors: W
authors: Lee
authors: E R
authors: ER
authors: Woo
authors: J S
authors: JS
authors: Choi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001682:Biological Availability; D002227:Carbazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000077261:Carvedilol; D045744:Cell Line, Tumor; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005419:Flavonoids / Q000008:administration & dosage*; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D011412:Propanolamines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123 / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000959:Antihypertensive Agents; D002227:Carbazoles; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D005456:Fluorescent Dyes; D011412:Propanolamines; D000077261:Carvedilol; D020112:Rhodamine 123; C040015:myricetin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019389:Cytochrome P-450 CYP2D6