title: Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John's wort ( Hypericum perforatum ).
abstract: Extracts of St. John's wort ( Hypericum perforatum ) became increasingly popular as easily available remedies for mild to moderate depression. Comedication with hypericum extract was recently shown to drastically reduce plasma concentration of ciclosporin, digoxin, and indinavir. We investigated the possible interaction of hypericum extract LI160 with amitriptyline. Both antidepressants have a high probability of concomitant use. Twelve patients requiring amitriptyline treatment received a single dose of hypericum extract (900 mg) at day 1, continued by a 12-to 14-day treatment with retarded amitriptyline (75 mg twice daily). Then hypericum (900 mg/day) was added for another 14 to 16 days. Steady-state pharmacokinetics of amitriptyline were compared before and after multiple-dose treatment with hypericum extract. Furthermore, comparisons were made for single-dose kinetics of hypericum-extract ingredients hypericin, pseudohypericin, and hyperforin between the first day of concomitant treatment and LI160 alone. Multiple-dose comedication with LI160 led to a statistically significant decrease in the area under the plasma concentration-time curve within one dosing interval of amitriptyline by 22% ( p = 0.03) and nortriptyline by 41% ( p = 0.002), as well as of all hydroxylated metabolites, except for 10-E-hydroxynortriptyline. Plasma levels of amitriptyline and hydroxylated metabolites gradually decreased, whereas nortriptyline concentrations were already markedly decreased after 3 days of cotreatment with hypericum. Cumulative urinary amounts of amitriptyline and metabolites decreased to the same extent as plasma concentrations upon hypericum comedication. Induction of cytochrome P-450 enzymes or drug transporters (P-glycoprotein) by St. John's wort extract may explain this pharmacokinetic interaction. Physicians should be aware of this interaction when treating patients with amitriptyline.
authors.affiliation: Institute of Clinical Pharmacology, University Medical Center Charité, Humboldt University of Berlin, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Johne
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schmider
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brockmöller
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Stadelmann
authors.forename: Elke
authors.initials: E
authors.lastname: Störmer
authors.forename: Steffen
authors.initials: S
authors.lastname: Bauer
authors.forename: Gudrun
authors.initials: G
authors.lastname: Scholler
authors.forename: Matthias
authors.initials: M
authors.lastname: Langheinrich
authors.forename: Ivar
authors.initials: I
authors.lastname: Roots
mesh_terms: D000328:Adult; D000639:Amitriptyline / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D003866:Depressive Disorder / Q000097:blood / Q000188:drug therapy* / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D020902:Hypericum; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D009661:Nortriptyline / Q000493:pharmacokinetics*; D008517:Phytotherapy / Q000009:adverse effects*; D010936:Plant Extracts / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics
chemical_list: C422326:Hypericum extract LI 160; D010936:Plant Extracts; D000639:Amitriptyline; D009661:Nortriptyline