Effects of St. John's wort on irinotecan metabolism.
St. John's wort (SJW), a widely used herbal product, has been implicated in drug interactions resulting from the induced expression of the cytochrome P450 CYP3A4 isoform. In this study, we determined the effect of SJW on the metabolism of irinotecan, a pro-drug of SN-38 and a known substrate for CYP3A4. Five cancer patients were treated with irinotecan (350 mg/m(2), intravenously) in the presence and absence of SJW (900 mg daily, orally for 18 days) in an unblinded, randomized crossover study design. The plasma levels of the active metabolite SN-38 decreased by 42% (95% confidence interval [CI] = 14% to 70%) following SJW cotreatment with 1.0 micro M x h (95% CI = 0.34 micro M x h to 1.7 micro M x h) versus 1.7 micro M x h (95% CI = 0.83 micro M x h to 2.6 micro M x h) (P =.033, two-sided paired Student's t test). Consequently, the degree of myelosuppression was substantially worse in the absence of SJW. These findings indicate that patients on irinotecan treatment should refrain from taking SJW because plasma levels of SN-38 were dramatically reduced, which may have a deleterious impact on treatment outcome.
Mathijssen
Ron H J
RH
Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
Verweij
Jaap
J
de Bruijn
Peter
P
Loos
Walter J
WJ
Sparreboom
Alex
A
D000928:Antidepressive Agents / Q000009:adverse effects; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002166:Camptothecin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000097:blood / Q000493:pharmacokinetics*; D016001:Confidence Intervals; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D020902:Hypericum / Q000009:adverse effects*; D000077146:Irinotecan; D006899:Mixed Function Oxygenases / Q000187:drug effects / Q000378:metabolism*; D059004:Topoisomerase I Inhibitors
D000928:Antidepressive Agents; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D002166:Camptothecin