Effect of St John's wort on imatinib mesylate pharmacokinetics.
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.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, USA. frye@cop.ufl.edu
Reginald F
RF
Frye
Sara M
SM
Fitzgerald
Theodore F
TF
Lagattuta
Matthew W
MW
Hruska
Merrill J
MJ
Egorin
D000284:Administration, Oral; D000328:Adult; D000928:Antidepressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001549:Benzamides; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006801:Humans; D020902:Hypericum; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D008517:Phytotherapy; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D010936:Plant Extracts / Q000009:adverse effects / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*
D000928:Antidepressive Agents; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D010936:Plant Extracts; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases