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


The primary objective of this study was to evaluate the effect of St. John's wort on the pharmacokinetics of imatinib in healthy volunteers. Compared with imatinib administered alone, imatinib given after 2 weeks of treatment with St. John's wort resulted in a significant reduction in imatinib exposure. The median AUC was reduced by 32%, Cmax was reduced by 29%, and half-life was reduced by 21%. The median apparent oral clearance increased from 13.8 to 20.3 L/hour. Imatinib was highly protein bound (~95%), and protein binding was not affected by the coadministration of St. John's wort.

The clinical significance of this interaction is potentially important. The observed reduction in imatinib exposure, measured by AUC, was approximately 32% on average and as high as 42%. In vitro studies and clinical trials of imatinib have found that clinical responses are correlated with dose and drug concentration, with a dosage of 400 mg/day generally superior to 300 mg/day and a dosage of 600 mg/day superior to 400 mg/day in patients with advanced disease.[2,14,15] The 25% difference between a daily dose of 300 versus 400 mg is less than the average reduction observed when imatinib was administered with St. John's wort. When potential metabolic contributions are disregarded, a 400-mg dose of imatinib administered with St. John's wort provided the same exposure as a 272-mg dose given alone.

One patient in a clinical trial failed to respond to imatinib therapy while taking phenytoin, an inducer of CYP3A4.[2] This patient had a very low AUC and experienced a complete response after discontinuing phenytoin and increasing the imatinib dosage. A drug interaction of this magnitude might contribute to imatinib resistance and treatment failure.[1]

Previous clinical studies and case reports have documented that St. John's wort lowers serum drug concentrations in patients taking numerous drugs that are metabolized by CYP3A4, such as cyclosporine, warfarin, oral contraceptives, theophylline, indinavir, amitriptyline, and nortriptyline.[16,17] These findings led to an FDA public health advisory in February 2000 warning against coadministration of St. John's wort with these agents.[18] Based on the results of this study, St. John's wort also should be avoided in patients treated with imatinib. In cases where St. John's wort is coadministered, a dosage increase or monitoring of imatinib concentrations might be considered.

One earlier drug-interaction study involved imatinib and rifampin in healthy adult volunteers.[19] In that study, the single-dose AUC0- of imatinib 400 mg and its primary active metabolite (CGP74588) were reduced by 74% and 12%, respectively, after administration of rifampin for 8 days. Rifampin is a potent inducer of CYP3A4, CYP2B6, CYP2C9, CYP2C19, and CYP2D6 metabolism, and it appears to be a more potent inducer than St. John's wort. The magnitude of the effect of St. John's Wort on the AUC of imatinib was generally similar to that reported for other CYP3A4 substrates, such as simvastatin,[20] nortriptyline,[21] fexofenadine,[22] and irinotecan[23]; somewhat less than the interaction reported for indinavir[17]; and greater than that reported for amitriptyline[21] and carbamazepine.[24]

In addition to the induction of CYP3A4 metabolism, recent data suggest that St. John's wort is an inducer of P-glycoprotein in the gastrointestinal tract[7] and that imatinib is a substrate for P-glycoprotein.[25] The observed reduction in the Cmax of imatinib may be a result of induction of P-glycoprotein or gastrointestinal CYP3A4, or both, by St. John's wort, leading to a reduction in bioavailability. Although CYP3A4 is the major enzyme responsible for imatinib metabolism, CYP1A2, CYP2D6, CYP2C9, and CYP2C19 could play minor roles.

In addition to the deleterious effect of St. John's wort on the pharmacokinetics of imatinib, the herbal product may affect the activity of imatinib in patients undergoing therapy for chronic leukemia. One of several resistance mechanisms of imatanib appears to be related to P-glycoprotein-mediated drug efflux in leukemia cells.[2,25] Some cells that are resistant to imatinib overexpress P-glycoprotein,[2,25,26] which is reversed through an increase in the intracellular accumulation of imatinib by P-glycoprotein inhibitors such as verapamil[26] and cyclosporine.[25] Thus, there is the potential for St. John's wort to reduce the activity of imatinib against leukemic cells through the induction of P-glycoprotein, leading to an increase in drug efflux. It is unknown whether this effect might be clinically relevant or observed differentially between wild-type cells and resistant cells that overexpress P-glycoprotein. Based on these concerns, there may be a deleterious pharmacodynamic interaction between St. John's wort and imatinib, in addition to the pharmacokinetic interaction.

St. John's wort did not alter the protein binding of imatinib over a wide range of concentrations in vivo. Thus, we are able to confirm that both free and total imatinib concentrations are reduced by St. John's wort. This may be important, as other reports have demonstrated a potential association between α1-acid glycoprotein concentrations and resistance both in vitro and in vivo.[27,28] Although controversial, these observations suggest that a reduction in free imatinib concentrations, induced by increasing α1-acid glycoprotein concentrations, may lead to imatinib resistance at clinically relevant concentrations.

The primary in vivo circulating metabolite of imatinib is CGP74588, an N-demethylated piperazine derivative that has demonstrated similar in vitro potency as the parent compound. The contribution of this metabolite to the overall activity of imatinib is unknown. Although we did not evaluate the effect of St. John's wort on the pharmacokinetics of CGP74588, the plasma AUC of this metabolite is 16% that of the imatinib AUC.[29] In addition, CGP74588 is a substrate of CYP3A4, which suggests that St. John's wort might induce the metabolism of this compound. In future drug-interaction studies involving imatinib and CYP3A4 inducers or inhibitors, investigators should attempt to further evaluate alterations in CGP74588 pharmacokinetics.

It is also apparent that certain individuals are more susceptible to the metabolic induction effects of St. John's wort. Subjects with the highest imatinib AUC at baseline experienced a greater reduction in imatinib exposure after the administration of St. John's wort. These findings suggest that some individuals have relatively low baseline CYP3A4 activity, which renders them more susceptible to the induction effects of drugs, placing them at higher risk for major drug interactions. This observation has been reported with drug interactions involving antiretroviral agents.[30]

It should be noted that this study did not involve direct observation of subjects ingesting St. John's wort. Compliance with the St. John's wort dosing regimen of 3 times/day, although reported to be excellent by all study participants, cannot be ensured. Hence, it is possible that the full induction capacity of St. John's wort on imatinib was not achieved in all subjects if compliance was less than 100%. It is also possible that patients undergoing imatinib therapy who have a substantially compromised health status compared with that of volunteers may exhibit greater changes than the one third decrease in imatinib exposure noted in this study.

St. John's wort is available as an over-the-counter dietary supplement in several formulations, produced by numerous manufacturers. As dietary supplements are not strictly regulated, the content and bioavailability of the active ingredients -- hyperforin and hypericin -- may vary considerably by product.[31] The formulation of St. John's wort that was used in this study was the same as that used in several National Institutes of Health studies, which demonstrated significant drug-drug interactions. Based on the differences in content and bioavailability of active ingredients in commercial St. John's wort products, the magnitude of this drug-drug interaction with imatinib may vary, making these interactions less predictable or consistent than those solely involving FDA-regulated prescription drugs.


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