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Blood, 15 August 2004, Vol. 104, No. 4, pp. 1229-1230.
CORRESPONDENCE To the editor:Induction of imatinib metabolism by hypericum perforatumHypericum perforatum (St John Wort) is an herbal preparation commonly used by cancer patients for mood elevation and is known to induce intestinal and hepatic cytochrome P450 3A4 (CYP3A4) and P-glycoprotein.1 CYP3A4 is the major isoenzyme responsible for imatinib metabolism, making imatinib potentially susceptible to drug interactions with numerous compounds, including hypericum perforatum.We evaluated the impact of hypericum perforatum on imatinib pharmacokinetics in an open label, fixed sequence, complete crossover study. There were 10 volunteers who received single doses of imatinib (400 mg) prior to and following 2 weeks of hypericum perforatum (300 mg) thrice daily. Imatinib plasma concentrations were determined at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours after dosing by liquid chromatography (LC)-tandem mass spectrometry (MS/MS). Free imatinib concentrations were measured at each 3- and 24-hour sample by ultrafiltration.
Imatinib pharmacokinetics were significantly altered by hypericum perforatum (Table 1). The median area under the curve (AUC0-
The clinical significance of this interaction appears to be important, with a median AUC reduction of 32% and as large as 42% in one subject. A 400-mg daily dose of imatinib is clinically superior to 300 mg (a 25% dose reduction), and 600 mg is superior to 400 mg in patients with advanced-phase disease.2-4 One patient in clinical trials also failed to respond to imatinib while taking phenytoin, another CYP3A4 inducer.3 This patient had a low imatinib AUC, and subsequently experienced a complete response following phenytoin discontinuation and an imatinib dosage increase. Therefore, a drug interaction of this magnitude might contribute to the development of imatinib resistance and treatment failures.5
One prior drug interaction study has evaluated the effect of a CYP3A4 inducer on imatinib. In a similar study design, rifampin decreased the single dose AUC0- The primary metabolite of imatinib, CGP74588 has similar in vitro potency as the parent compound, although the plasma AUC is only 16% of the imatinib AUC.7 While we did not measure CGP74588 it is also a CYP3A4 substrate, and therefore may be similarly induced by hypericum perforatum coadministration. It should also be noted that we did not use directly observed ingestion of hypericum perforatum, and compliance, although reported to be excellent by participants, cannot be ensured. It is therefore possible that the full induction capacity of hypericum perforatum on imatinib was not achieved in all subjects. It is also possible that chronic leukemia patients undergoing imatinib treatment may exhibit greater changes in imatinib exposure compared with healthy volunteers. Clinicians and patients should be aware of the potential interactions that exist between herbal products and anticancer agents, and take appropriate steps to ensure that such interactions do not unnecessarily compromise therapeutic outcomes. Clinicians should be aware that hypericum perforatum may reduce imatinib exposure by 30% to 40% and take appropriate actions to educate patients receiving imatinib treatment.
Correspondence: Patrick F. Smith, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263; e-mail: pfsmith{at}buffalo.edu.
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| Copyright © 2004 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
) decreased by 32% (28.9 vs 19.7 µg x h/mL), with maximum concentration (Cmax) and half-life reduced by 29% and 21%, respectively. Imatinib was approximately 95% protein bound (with little intersubject variability), concentration independent, and not altered by hypericum perforatum. 
