title: Lack of a clinically significant interaction of grapefruit juice with ambrisentan and bosentan in healthy adults.
abstract: OBJECTIVE
  We assessed the effect of 1 x 300 mL/d and 3 x 300 mL/d grapefruit juice (GFJ) on ambrisentan and bosentan pharmacokinetics in healthy volunteers.
  
  
  METHODS
  In the ambrisentan study, 12 healthy extensive metabolizers (EM) of CYP2C19 received therapeutic doses of ambrisentan (5 mg q.d. on study days 1 - 11) and GFJ (1 x 300 mL/d on study days 6 - 8 and 3 x 300 mL/d on study days 9 - 11). Ambrisentan pharmacokinetics was assessed on study days 5, 8, and 11. In the bosentan study, 16 healthy EM of CYP2C9, who were stratified into two groups (CYP3A5 expressors (n = 8) and CYP3A5 non-expressors (n = 8)), received bosentan (125 mg b.i.d. on study days 1 - 13) and GFJ (1 x 300 mL/d on study days 8 - 10 and 3 x 300 mL/d on study days 11 - 13). Bosentan pharmacokinetics was assessed on study days 7, 10, and 13.
  
  
  RESULTS
  Whereas 1 x 300 mL/d GFJ had no effect on the pharmacokinetics of ambrisentan and its metabolite, 3 x 300 mL/d GFJ increased the exposure with ambrisentan by 8% and the molar plasma metabolic ratio by 22% (both p < 0.05). Correspondingly, the apparent oral clearance of ambrisentan decreased to 92% (p < 0.05). GFJ slightly prolonged t(max) of bosentan and increased the metabolic ratio of bosentan/hydroxy-bosentan by 19% (p < 0.05).
  
  
  CONCLUSIONS
  GFJ had no clinically relevant effect on the pharmacokinetics or safety profile of ambrisentan and bosentan. Therefore, no dose adjustments are needed, and GFJ can be safely co-administered even at very high doses.
authors.forename: Christoph
authors.initials: C
authors.lastname: Markert
authors.forename: Theresia
authors.initials: T
authors.lastname: Wirsching
authors.forename: Regina
authors.initials: R
authors.lastname: Hellwig
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Riedel
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
authors.forename: Walter E
authors.initials: WE
authors.lastname: Haefeli
mesh_terms: D000328:Adult; D000077300:Bosentan; D032083:Citrus paradisi; D005260:Female; D018565:Food-Drug Interactions; D000067030:Fruit and Vegetable Juices; D006801:Humans; D008297:Male; D010666:Phenylpropionates / Q000009:adverse effects / Q000493:pharmacokinetics*; D011724:Pyridazines / Q000009:adverse effects / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D010666:Phenylpropionates; D011724:Pyridazines; D013449:Sulfonamides; C467894:ambrisentan; D000077300:Bosentan