Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans.
OBJECTIVE
Phytochemical-mediated modulation of cytochrome P450 (CYP) activity may underlie many herb-drug interactions. Single-time point phenotypic metabolic ratios were used to determine whether long-term supplementation of St John's wort, garlic oil, Panax ginseng, and Ginkgo biloba affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity.


METHODS
Twelve healthy volunteers (6 females) were randomly assigned to receive either St John's wort, garlic oil, P ginseng, or G biloba for 28 days. For each subject, a 30-day washout period was interposed between each supplementation phase. Probe-drug cocktails of midazolam, caffeine, chlorzoxazone, and debrisoquin (INN, debrisoquine) were administered before supplementation (baseline) and at the end of supplementation. Presupplementation and postsupplementation phenotypic trait measurements were determined for CYP3A4, CYP1A2, CYP2E1, and CYP2D6 with the use of 1-hydroxymidazolam/midazolam serum ratios (1-hour sample), paraxanthine/caffeine serum ratios (6-hour sample), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour sample), and debrisoquin urinary recovery ratios (8-hour collection), respectively.


RESULTS
Comparisons of presupplementation and postsupplementation ratios indicated that St John's wort significantly induced the activity of CYP2E1 and CYP3A4 (P <.0001). Among female subjects, St John's wort produced significantly greater increases in CYP3A4 phenotypic ratios that appeared to be unrelated to body mass index. This finding is suggestive of a sexual dimorphism in CYP3A4 inducibility. Garlic oil reduced CYP2E1 activity by 39% (P =.030), whereas no significant effect on CYP activity was observed for P ginseng and G biloba.


CONCLUSIONS
Single-time point phenotypic metabolic ratios may provide a practical means of predicting CYP-mediated herb-drug interactions in humans.
Gurley
Bill J
BJ
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, 72205, USA. gurleybillyj@uams.edu
Gardner
Stephanie F
SF
Hubbard
Martha A
MA
Williams
D Keith
DK
Gentry
W Brooks
WB
Cui
Yanyan
Y
Ang
Catharina Y W
CY
D000328:Adult; D000498:Allyl Compounds / Q000493:pharmacokinetics; D000704:Analysis of Variance; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004347:Drug Interactions / Q000235:genetics; D005260:Female; D020441:Ginkgo biloba / Q000378:metabolism; D041743:Herb-Drug Interactions; D006801:Humans; D020902:Hypericum / Q000378:metabolism; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D005894:Panax / Q000378:metabolism; D010641:Phenotype; D008517:Phytotherapy / Q000379:methods; D028321:Plant Preparations / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011237:Predictive Value of Tests; D012737:Sex Factors; D013440:Sulfides / Q000493:pharmacokinetics
D000498:Allyl Compounds; D028321:Plant Preparations; D013440:Sulfides; C038491:allyl sulfide; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human