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Vol. 294, Issue 1, 88-95, July 2000
Drug Metabolism Department, Candidate Synthesis, Enhancement, and
Evaluation, Central Research Division, Pfizer, Inc., Groton,
Connecticut
Commercially available St. John's wort (Hypericum
perforatum) extracts, preparations that are used in the
treatment of depression, were examined for the potential to inhibit
human cytochrome P450 (CYP) enzyme activities, specifically CYP1A2,
CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Crude extracts demonstrated
inhibition of each of these five enzymes, with CYP2D6, CYP2C9, and
CYP3A4 being more sensitive than CYP1A2 and CYP2C19. Extracts were
fractionated by HPLC, and each of the fractions was tested for
inhibition of these five CYPs to identify individual constituents with
inhibitory activity. Several fractions were shown to possess inhibitory
activity, including the fractions containing hyperforin (the putative
active antidepressant constituent), I3,II8-biapigenin, and hypericin. Hyperforin and I3,II8-biapigenin were isolated from the extract, and
inhibition constants for the five CYP activities were measured. In
addition, three other constituents, hypericin, quercetin, and chlorogenic acid, were tested for inhibitory activity toward the CYP
enzymes. The flavonoid compound I3,II8-biapigenin was shown to be a
potent, competitive inhibitor of CYP3A4, CYP2C9, and CYP1A2 activities
with Ki values of 0.038, 0.32, and 0.95 µM, respectively. Hyperforin was a potent noncompetitive inhibitor of
CYP2D6 activity (Ki = 1.5 µM) and
competitive inhibitor of CYP2C9 and CYP3A4 activities (Ki = 1.8 and 0.48 µM, respectively).
Hypericin also demonstrated potent inhibition of several CYP
activities. These in vitro data indicate that St. John's wort
preparations contain constituents that can potently inhibit the
activities of major human drug-metabolizing enzymes and suggest that
these preparations should be examined for potential pharmacokinetic
drug interactions in vivo.
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