Effect of the St. John's wort constituent hyperforin on docetaxel metabolism by human hepatocyte cultures.
OBJECTIVE
St. John's wort is a commonly used herbal medication that increases cytochrome P450 3A (CYP3A) activity. Because docetaxel is inactivated by CYP3A, we studied the effects of the St. John's wort constituent hyperforin on docetaxel metabolism in a human hepatocyte model.


METHODS
Hepatocytes, isolated from three donor livers, were exposed to hyperforin (0.1, 0.5, or 1.5 micromol/L) or rifampin (10 micromol/L) for 48 hours. After 48 hours, hyperforin- or rifampin-containing medium was replaced with medium containing 100 micromol/L docetaxel. After 1 hour, docetaxel metabolism was characterized by liquid chromatography-tandem mass spectrometry. Subsequent incubations characterized the specific cytochrome P450s that produced the docetaxel metabolites observed in hepatocyte incubations.


RESULTS
Rifampin induced docetaxel metabolism 6.8- to 32-fold above docetaxel metabolism in control cultures. Hyperforin induced docetaxel metabolism in all three hepatocyte preparations. Hyperforin induction was dose-dependent and, at maximum, was 2.6- to 7-fold greater than that in controls. Docetaxel metabolites identified in rifampin- and hyperforin-treated hepatocyte preparations included the previously described tert-butyl-hydroxylated metabolite and two previously unidentified metabolites involving hydroxylation on the baccatin ring. CYP3A4 produced the tert-butyl-hydroxylated metabolite and the two ring-hydroxylated metabolites. CYP2C8 produced one of the newly described ring-hydroxylated metabolites.


CONCLUSIONS
Exposure to the St. John's wort constituent hyperforin induces docetaxel metabolism in vitro. This implies that subtherapeutic docetaxel concentrations may result when docetaxel is administered to patients using St. John's wort on a chronic basis. The results also show induction of previously undescribed metabolic pathways for docetaxel, one of which may be analogous to the known 6-alpha-hydroxylation of paclitaxel by CYP2C8.
Komoroski
Bernard J
BJ
Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pennsylvania 15213-1863, USA.
Parise
Robert A
RA
Egorin
Merrill J
MJ
Strom
Stephen C
SC
Venkataramanan
Raman
R
D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002853:Chromatography, Liquid; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000077143:Docetaxel; D004357:Drug Synergism; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020902:Hypericum / Q000378:metabolism*; D007477:Ions; D008099:Liver / Q000378:metabolism; D013058:Mass Spectrometry; D008875:Middle Aged; D008956:Models, Chemical; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology; D043823:Taxoids / Q000494:pharmacology*; D013729:Terpenes / Q000494:pharmacology*; D013997:Time Factors
D000970:Antineoplastic Agents; D001643:Bridged Bicyclo Compounds; D007477:Ions; D043823:Taxoids; D013729:Terpenes; D000077143:Docetaxel; D003577:Cytochrome P-450 Enzyme System; D010696:Phloroglucinol; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C001654:hyperforin; D012293:Rifampin