title: The effect of induction of CYP3A4 by St John's wort on ambrisentan plasma pharmacokinetics in volunteers of known CYP2C19 genotype.
abstract: To evaluate the impact of CYP2C19 polymorphisms on ambrisentan exposure and to assess its modification by St. John's wort (SJW), 20 healthy volunteers (10 CYP2C19 extensive, four poor and six ultrarapid metabolizers) received therapeutic doses of ambrisentan (5 mg qd po) for 20 days and concomitantly SJW (300 mg tid po) for the last 10 days. To quantify changes of CYP3A4 activity, midazolam (3 mg po) as a probe drug was used. Ambrisentan pharmacokinetics was assessed on days 1, 10 and 20, and midazolam pharmacokinetics before and on days 1, 10, 17 and 20. At steady state, ambrisentan exposure was similar in extensive and ultrarapid metabolizers but 43% larger in poor metabolizers (p < 0.01). In all volunteers, SJW reduced ambrisentan exposure and the relative change (17-26%) was similar in all genotype groups. The extent of this interaction did not correlate with the changes in CYP3A activity (midazolam clearance) (rs = 0.23, p = 0.34). Ambrisentan had no effect on midazolam pharmacokinetics. In conclusion, SJW significantly reduced exposure with ambrisentan irrespective of the CYP2C19 genotype. The extent of this interaction was small and thus likely without clinical relevance.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Markert
authors.forename: Ida Maria
authors.initials: IM
authors.lastname: Kastner
authors.forename: Regina
authors.initials: R
authors.lastname: Hellwig
authors.forename: Peter
authors.initials: P
authors.lastname: Kalafut
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schweizer
authors.forename: Michael Marcus
authors.initials: MM
authors.lastname: Hoffmann
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
authors.forename: Walter Emil
authors.initials: WE
authors.lastname: Haefeli
mesh_terms: D000284:Administration, Oral; D000328:Adult; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D065701:Cytochrome P-450 CYP3A Inducers / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D004790:Enzyme Induction; D005260:Female; D005838:Genotype; D005858:Germany; D064368:Healthy Volunteers; D041743:Herb-Drug Interactions; D006801:Humans; D020902:Hypericum; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics; D010597:Pharmacogenetics; D010641:Phenotype; D010666:Phenylpropionates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D010936:Plant Extracts / Q000008:administration & dosage*; D011724:Pyridazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D065701:Cytochrome P-450 CYP3A Inducers; D010666:Phenylpropionates; D010936:Plant Extracts; D011724:Pyridazines; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C467894:ambrisentan; D008874:Midazolam