title: In vitro inhibition of metabolism but not transport of gliclazide and repaglinide by Cree medicinal plant extracts.
abstract: BACKGROUND
  Interactions between conventional drug and traditional medicine therapies may potentially affect drug efficacy and increase the potential for adverse reactions. Cree traditional healing is holistic and patients may use medicinal plants simultaneously with the conventional drugs. However, there is limited information that these medicinal plants may interact with drugs and additional mechanistic information is required. In this study, extracts from traditionally used Cree botanicals were assessed for their potential interaction that could alter the disposition of two blood glucose lowering drugs, gliclazide (Diamicron) and repaglinide (Gluconorm) though inhibition of either metabolism or transport across cell membranes.
  
  
  METHODS
  The effect of 17 extracts on metabolism was examined in a human liver microsome assay by HPLC and individual cytochrome P450s 2C9, 2C19, 2C8 and 3A4 in a microplate fluorometric assay. Gliclazide, rhaponticin and its aglycone derivative, rhapontigenin were also examined in the fluorometric assay. The effect on transport was examined with 11 extracts using the intestinal epithelial Caco-2 differentiated cell monolayer model at times up to 180 min.
  
  
  RESULTS
  Both blood glucose lowering medications, gliclazide and repaglinide traversed the Caco-2 monolayer in a time-dependent manner that was not affected by the Cree plant extracts. Incubation of the Cree plant extracts inhibited CYP2C9, 2C19, 2C8 and 3A4-mediated metabolism, and the formation of four repaglinide metabolites: M4, m/z 451-A, m/z 451-B and the glucuronide of repaglinide in the human liver microsome assay. Gliclazide caused no significant inhibition. Likewise, rhaponticin had little effect on the enzymes causing changes of less than 10% with an exception of 17% inhibition of CYP2C19. By contrast, the aglycone rhapontigenin showed the greatest effects on all CYP-mediated metabolism. Its inhibition ranged from a mean of 58% CYP3A4 inhibition to 89% inhibition of CYP2C9. While rhaponticin and the aglycone did not show significant effects on repaglinide metabolism, they demonstrated inhibition of gliclazide metabolism. The aglycone significantly affected levels of gliclazide and its metabolites.
  
  
  CONCLUSIONS
  These studies demonstrate that the Cree plant extracts examined have the potential in vitro to cause drug interactions through effects on key metabolic enzymes.
authors.affiliation: Biology Department, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5.
authors.forename: Carolina
authors.initials: C
authors.lastname: Cieniak
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Alexandra
authors.initials: A
authors.lastname: Fottinger
authors.forename: Sheila A M
authors.initials: SA
authors.lastname: Smiley
authors.forename: Jose A
authors.initials: JA
authors.lastname: Guerrero-Analco
authors.forename: Steffany A L
authors.initials: SA
authors.lastname: Bennett
authors.forename: Pierre S
authors.initials: PS
authors.lastname: Haddad
authors.forename: Alain
authors.initials: A
authors.lastname: Cuerrier
authors.forename: Ammar
authors.initials: A
authors.lastname: Saleem
authors.forename: John T
authors.initials: JT
authors.lastname: Arnason
authors.forename: Brian C
authors.initials: BC
authors.lastname: Foster
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018938:Caco-2 Cells; D002219:Carbamates / Q000494:pharmacology*; D004347:Drug Interactions; D005907:Gliclazide / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007408:Intestinal Absorption; D008519:Medicine, Traditional; D008862:Microsomes, Liver / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology*; D010946:Plants, Medicinal; D011792:Quebec; D013267:Stilbenes / Q000378:metabolism
chemical_list: D002219:Carbamates; D007004:Hypoglycemic Agents; D010880:Piperidines; D010936:Plant Extracts; D013267:Stilbenes; C431126:rhapontigenin; C072379:repaglinide; D001189:Aryl Hydrocarbon Hydroxylases; D014453:Glucuronosyltransferase; D005907:Gliclazide
keywords: Caco-2; Cytochrome P450; Disposition; Drug interaction; Traditional medicine