Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum)

Clin Pharmacol Ther. 1999 Oct;66(4):338-45. doi: 10.1053/cp.1999.v66.a101944.


Objective: Extracts of St John's wort (Hypericum perforatum) are widely used in the treatment of depression, often as an over-the-counter drug. In contrast to its frequent use, knowledge about the pharmacokinetics of ingredients and drug interactions of St John's wort is poor. We studied the interaction between hypericum extract LI160 and digoxin.

Methods: The pharmacokinetics of digoxin were investigated in a single-blind, placebo-controlled parallel study. After the achievement of steady state for digoxin on day 5, healthy volunteers received digoxin (0.25 mg/d) either with placebo (n = 12) or with 900 mg/d LI160 (n = 13) for another 10 days. Digoxin concentration profiles on day 5 were compared with day 6 (single-dose interaction) and day 15 (tenth day of co-medication).

Results: There was a highly significant combined-day-and-group effect for digoxin area under the plasma concentration-time curve [AUC(0-24); P = .0001], peak concentration in plasma (Cmax; P = .0001), and plasma drug concentration at the end of a dosing interval (P = .0003) by two-way ANOVA. No statistically significant change was observed after the first dose of hypericum extract [AUC(0-24) at day 6 of 18.1+/-2.9 microg x h/L and 17.7+/-3.0 microg x h/L, mean +/- SD for placebo and hypericum group, respectively]. However, 10 days of treatment with hypericum extract resulted in a decrease of digoxin AUC(0-24) by 25% (day 15, 17.2+/-4.0 microg x h/L and 12.9+/-2.3 microg x h/L; P = .0035). Furthermore, comparison with the parallel placebo group after multiple dosing showed a reduction in trough concentrations and Cmax of 33% (P = .0023) and 26% (P = .0095), respectively. The effect became increasingly pronounced until the tenth day of co-medication.

Conclusion: As with grapefruit juice, a food product, physicians should also be aware of potential drug-herb interactions. The interaction of St John's wort extract with digoxin kinetics was time dependent. The mechanism involved may be induction of the P-glycoprotein drug transporter.

Publication types

  • Clinical Trial
  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Analysis of Variance
  • Anti-Arrhythmia Agents / blood
  • Anti-Arrhythmia Agents / pharmacokinetics*
  • Antidepressive Agents / adverse effects*
  • Antidepressive Agents / therapeutic use
  • Area Under Curve
  • Cardiotonic Agents / blood
  • Cardiotonic Agents / pharmacokinetics*
  • Digoxin / blood
  • Digoxin / pharmacokinetics*
  • Drug Administration Schedule
  • Female
  • Humans
  • Hypericum / adverse effects*
  • Hypericum / therapeutic use
  • Male
  • Phytotherapy
  • Plants, Medicinal*
  • Reference Values
  • Single-Blind Method
  • Time Factors


  • Anti-Arrhythmia Agents
  • Antidepressive Agents
  • Cardiotonic Agents
  • Digoxin