The Influence of St. John's Wort on the Pharmacokinetics and Protein Binding of Imatinib Mesylate

Patrick F. Smith, Pharm.D.; Julie M. Bullock, Pharm.D.; Brent M. Booker, Pharm.D.; Curtis E. Haas, Pharm.D.; Charles S. Berenson, M.D.; William J. Jusko, Ph.D.


Pharmacotherapy. 2004;24(11) 

In This Article

Abstract and Introduction

Study Objective: To determine the effect of St. John's wort on the pharmacokinetics of imatinib mesylate.
Design: Open-label, complete crossover, fixed-sequence, pharmacokinetic study.
Setting: Clinical research center.
Subjects: Ten healthy adult volunteers.
Intervention: Single 400-mg oral doses of imatinib were administered before and after 2 weeks of treatment with St. John's wort 300 mg 3 times/day.
Measurements and Main Results: The pharmacokinetics of imatinib were significantly altered by St. John's wort, with reductions of 32% in the median area under the concentration-time curve from time zero to infinity (p=0.0001), 29% in maximum observed concentration (p=0.005), and 21% in half-life (p=0.0001). Protein binding ranged from 97.7-90.3% (mean 94.9%), was concentration independent, and was not altered by St. John's wort. Therapeutic outcomes of imatinib have been shown to correlate with both dose and drug concentrations.
Conclusion: Coadministration of imatinib with St. John's wort may compromise imatinib's clinical efficacy.

Imatinib mesylate (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) recently received expedited approval in the United States as an orphan drug for the treatment of chronic myeloid leukemia, and it has rapidly become a cornerstone of therapy. However, this accelerated approval has been accompanied by a relative lack of drug-interaction studies typical of the standard drug-development process. Drug interactions with imatinib are of particular clinical concern, as this agent is metabolized primarily by cytochrome P450 (CYP) 3A4,[1] making it susceptible to significant increases or decreases in systemic exposure by the many agents known to alter CYP3A4 activity. Therapeutic outcomes have been shown to correlate with both dose and drug concentrations[2]; therefore, coadministered agents that alter imatinib metabolism may significantly compromise the clinical efficacy of this important new therapy.

The use of alternative medicine has increased tremendously over the last decade and is particularly common in patients with cancer. Recent surveys have reported that approximately one third to one half of these patients use some type of alternative medicine, such as vitamins and herbal products.[3,4,5] Because patients may not consider these alternative products to be drugs, they frequently do not report their use of such agents to their physician or pharmacist.

St. John's wort is commonly used for mood elevation in patients with cancer[6] and is known to induce both CYP3A4 and P-glycoprotein.[7,8] It appears that hyperforin, the active component of St. John's wort, binds and activates the pregnane X receptor, resulting in an increase in messenger RNA expression of CYP3A4.[9] Therefore, a significant drug interaction could result in patients being treated with imatinib and concurrently taking St. John's wort.

The objective of this study was to evaluate the effect of St. John's wort on the pharmacokinetics of imatinib. A brief report of the induction of imatinib metabolism by St. John's wort has been published previously.[10]


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