Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St John's wort, garlic oil, Panax ginseng and Ginkgo biloba.
OBJECTIVE
Elderly patients are more likely to ingest prescription medications concurrently with botanical supplements, and may therefore be vulnerable to herb-drug interactions. Phytochemical-mediated modulation of cytochrome P450 (CYP) activity may underlie many herb-drug interactions. Some evidence suggests that CYP activity may decrease in the elderly. If so, herb-mediated changes in CYP activity may take on greater clinical relevance in this population. In this study, single timepoint, 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 in elderly subjects.


METHODS
Twelve healthy volunteers between the ages of 60 and 76 years (mean age 67 years) were randomly assigned to receive each botanical supplement for 28 days followed by a 30-day washout period. Probe drug cocktails of midazolam, caffeine, chlorzoxazone and debrisoquine were administered before and at the end of supplementation. Pre- and post-supplementation phenotypic ratios were determined for CYP3A4, CYP1A2, CYP2E1 and CYP2D6 using 1-hydroxymidazolam/midazolam serum ratios (1-hour), paraxanthine/caffeine serum ratios (6-hour), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour) and debrisoquine urinary recovery ratios (8-hour), respectively. The content of purported 'active' phytochemicals was determined for each supplement.


RESULTS
Comparisons of pre- and post-St John's wort phenotypic ratios revealed significant induction of CYP3A4 (approximately 140%) and CYP2E1 activity (approximately 28%). Garlic oil inhibited CYP2E1 activity by approximately 22%. P. ginseng inhibition of CYP2D6 was statistically significant, but the magnitude of the effect (approximately 7%) did not appear to be clinically relevant. None of the supplements tested in this study appeared to affect CYP1A2 activity.


CONCLUSIONS
Elderly subjects, like their younger counterparts, are susceptible to herb-mediated changes in CYP activity, especially those involving St John's wort. Pharmacokinetic herb-drug interactions stemming from alterations in CYP activity may adversely affect drug efficacy and/or toxicity. When compared with earlier studies that employed young subjects, the data suggest that some age-related changes in CYP responsivity to botanical supplementation may exist. Concomitant ingestion of botanical supplements with prescription medications, therefore, should be strongly discouraged in the elderly.
Gurley
Bill J
BJ
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 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
D000284:Administration, Oral; D000368:Aged; D000498:Allyl Compounds / Q000737:chemistry; D002110:Caffeine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D002753:Chlorzoxazone / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D019587:Dietary Supplements; D004334:Drug Administration Schedule; D005260:Female; D020441:Ginkgo biloba / Q000737:chemistry; D041743:Herb-Drug Interactions; D006801:Humans; D020902:Hypericum / Q000737:chemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D005894:Panax / Q000737:chemistry; D010641:Phenotype; D028321:Plant Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013440:Sulfides / Q000737:chemistry
D000498:Allyl Compounds; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D028321:Plant Preparations; D013440:Sulfides; D002110:Caffeine; C038491:allyl sulfide; D003577:Cytochrome P-450 Enzyme System; D002753:Chlorzoxazone; D008874:Midazolam