Objective: Imatinib is a potent inhibitor of the Bcr-Abl and c- kit tyrosine kinases and is approved for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia and gastrointestinal stromal tumors. Because imatinib is predominantly metabolized by cytochrome P450 (CYP) 3A4, its pharmacokinetics may be altered when it is coadministered with drugs or herbs (eg, St John's wort) that modulate CYP3A4 activity. Thus we examined the effects of St John's wort on imatinib pharmacokinetics.
Methods: This 2-period, open-label, fixed-sequence study was completed by 12 healthy subjects (6 men and 6 women) aged between 20 and 51 years. Each subject received 400 mg imatinib orally on study day 1, St John's wort (300 mg 3 times daily) on days 4 to 17, and 400 mg imatinib again on day 15. Serial blood samples were obtained over a 72-hour period after each imatinib dose. Imatinib and N -desmethyl-imatinib (CGP 74588) were quantified in plasma by liquid chromatography-mass spectrometry.
Results: St John's wort administration increased imatinib clearance by 43% ( P < .001), from 12.5 +/- 3.6 L/h to 17.9 +/- 5.6 L/h; imatinib area under the concentration versus time curve (AUC) extrapolated to infinity was decreased by 30%, from 34.5 +/- 9.5 microg . h/mL to 24.2 +/- 7.0 microg . h/mL ( P < .001). Imatinib half-life (12.8 hours versus 9.0 hours) and maximum concentration (C max ) (2.2 microg/mL versus 1.8 microg/mL) were also significantly decreased ( P < .005). N -desmethyl-imatinib C max was increased from 285 +/- 95 ng/mL to 318 +/- 95 ng/mL during St John's wort dosing, but the AUC from 0 to 72 hours was not altered.
Conclusions: These data indicate that St John's wort increases imatinib clearance. Thus patients taking imatinib should avoid taking St John's wort. Concomitant use of enzyme inducers, including St John's wort, may necessitate an increase in the imatinib dose to maintain clinical effectiveness.