The Effect of Induction of CYP3A4 by St John's Wort on Ambrisentan Plasma Pharmacokinetics in Volunteers of known CYP2C19 Genotype. (8th November 2014)

• Record Type: Journal Article
• Authors: Markert, Christoph; Kastner, Ida Maria; Hellwig, Regina; Kalafut, Peter; Schweizer, Yvonne; Hoffmann, Michael Marcus; Burhenne, Jürgen; Weiss, Johanna; Mikus, Gerd; Haefeli, Walter Emil
• Is Part Of: Basic & clinical pharmacology & toxicology. Volume 116:Number 5(2015:May)
• Page Start: 423
• Page End: 428
• Publication Date: 2014-11-08
• Subjects: Pharmacology -- Periodicals; Toxicology -- Periodicals; Pharmacology -- Periodicals; Toxicology -- Periodicals; Pharmacology, Clinical -- Periodicals; Computer network resources; Electronic journals; 615.1
• DOI: 10.1111/bcpt.12332
• Languages: English
• ISSNs: 1742-7835

Abstract

<abstract abstract-type="main" id="bcpt12332-abs-0001"> <title>Abstract</title> <p>To evaluate the impact of <italic>CYP2C19</italic> polymorphisms on ambrisentan exposure and to assess its modification by St. John's wort (SJW), 20 healthy volunteers (10 <italic>CYP2C19</italic> 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 (<italic>p</italic> &lt; 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) (<italic>r</italic>_s = 0.23, <italic>p</italic> = 0.34). Ambrisentan had no effect on midazolam pharmacokinetics. In conclusion, SJW significantly reduced exposure with ambrisentan irrespective of the <italic>CYP2C19</italic> genotype. The extent of this interaction was small and thus likely without clinical relevance.</p> </abstract>