Goldenseal (Hydrastis canadensis)
In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4 phenotypes
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Objectives— Phytochemical-mediated modulation of cytochrome P-450 activity may underlie many herb-drug interactions. Single time-point, phenotypic metabolic ratios were used to determine whether long-term supplementation of goldenseal (Hydrastis canadensis), black cohosh (Cimicifuga racemosa), kava kava (Piper methysticum), or valerian (Valeriana officinalis) extracts affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4/5 activity.
Methods— Twelve healthy volunteers (6 females) were randomly assigned to receive goldenseal, black cohosh, kava kava, or valerian for 28 days. For each subject, a 30-day washout period was interposed between each supplementation phase. Probe drug cocktails of midazolam and caffeine, followed 24 hours later by chlorzoxazone and debrisoquine were administered before (baseline) and at the end of supplementation. Pre- and post-supplementation phenotypic trait measurements were determined for CYP3A4/5, CYP1A2, CYP2E1, and CYP2D6 using 1-hydroxymidazolam/midazolam serum ratios (1-hour sample), paraxanthine/caffeine serum ratios (6-hour sample), 6- hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour sample), and debrisoquine urinary recovery ratios (8-hour collection), respectively. The content of purported “active” phytochemicals was determined for each supplement.
Results— Comparisons of pre- and post-supplementation phenotypic ratio means revealed significant inhibition (~40%) of CYP2D6 (difference = −0.228; 95% CI = −0.268 to −0.188) and CYP3A4/5 (difference = −1.501; 95% CI = −1.840 to −1.163) activity for goldenseal. Kava produced significant reductions (~40%) in CYP2E1 only (difference = −0.192; 95% CI = −0.325 to −0.060). Black cohosh also exhibited statistically significant inhibition of CYP2D6 (difference = −0.046; 95% CI = −0.085 to −0.007), but the magnitude of the effect (~7%) did not appear clinically relevant. No significant changes in phenotypic ratios were observed for valerian.
Conclusions— Botanical supplements containing goldenseal strongly inhibited CYP2D6 and CYP3A4/5 activity in vivo, while kava inhibited CYP2E1 and black cohosh weakly inhibited CYP2D6. Accordingly, serious adverse interactions may result from the concomitant ingestion of goldenseal supplements and drugs that are CYP2D6 and CYP3A4/5 substrates. Kava kava and black cohosh may interact with CYP2E1 and CYP2D6 substrates, respectively. Valerian appears less likely to produce CYP-mediated herb-drug interactions.
1 . CYP2D6 Experiment (id=NPDI-fDeLbA)
In Vivo Interaction Study
Increased systemic exposure was detected.
- CYP2D6 4173631
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Probe cocktail study
Fixed-sequence
Multiple dosing
Females
Healthy volunteers
Males
Nonsmokers
CYP2D6 ultra-rapid metabolizer
12
(6 females) (age, mean ± SD = 24 ± 3.0 years; weight, 69.3 ± 14.2 kg)
8 hours
Drug or Natural Product Administration
Oral
solution
4 mg
once
twice in 28 day trial
Oral
capsule
2700 mg
three times daily
28 days
Wild Oats Markets, Inc. Boulder, CO.
not specified
Pharmacodynamics (PD) & Adverse Events
Gastrointestinal disorders
35700000
General disorders and administration site conditions
35800000
Headache (4 of 12 subjects) and nausea (3 of 12 subjects)
2 . CYP3A4 Experiment (id=NPDI-Bi2fGw)
Results
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Probe cocktail study
Fixed-sequence
Multiple dosing
Females
Healthy volunteers
Males
Nonsmokers
CYP2D6 ultra-rapid metabolizer
12
(6 females) (age, mean ± SD = 24 ± 3.0 years; weight, 69.3 ± 14.2 kg)
Did not use botanical dietary supplements or non-prescription/prescription medications aside from oral contraception in the female group, which they continued.
All females had a negative prenancy test at baseline
1 and 6 hours
Drug or Natural Product Administration
Oral
not specified
8 mg
once
twice in 28 day trial
Oral
capsule
2700 mg
three times daily
28 days
Wild Oats Markets, Inc. Boulder, CO.
not specified
Pharmacodynamics (PD) & Adverse Events
Gastrointestinal disorders
35700000
General disorders and administration site conditions
35800000
Headache (4 of 12 subjects) and nausea (3 of 12 subjects)
3 . CYP1A2 Experiment (id=NPDI-T6Zq4Q)
In Vivo Interaction Study
No Effect (based on bioequivalence limits) was detected.
caffeine 1134439
- CYP1A2 4312402
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Probe cocktail study
Fixed-sequence
Multiple dosing
Females
Healthy volunteers
Males
Nonsmokers
CYP2D6 ultra-rapid metabolizer
12
(6 females) (age, mean ± SD = 24 ± 3.0 years; weight, 69.3 ± 14.2 kg)
Did not use botanical dietary supplements or non-prescription/prescription medications aside from oral contraception in the female group, which they continued.
All females had a negative prenancy test at baseline
1 and 6 hours
Drug or Natural Product Administration
Oral
solution
100 mg
once
twice in 28 day trial
Oral
capsule
2700 mg
three times daily
28 days
Wild Oats Markets, Inc. Boulder, CO.
not specified
Pharmacodynamics (PD) & Adverse Events
Gastrointestinal disorders
35700000
General disorders and administration site conditions
35800000
Headache (4 of 12 subjects) and nausea (3 of 12 subjects)
4 . CYP2E1 Experiment (id=NPDI-Vt7rHw)
In Vivo Interaction Study
No Effect (based on bioequivalence limits) was detected.
- CYP2E1 4173608
Results
Table 1
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Probe cocktail study
Fixed-sequence
Multiple dosing
Females
Healthy volunteers
Males
Nonsmokers
CYP2D6 ultra-rapid metabolizer
12
(6 females) (age, mean ± SD = 24 ± 3.0 years; weight, 69.3 ± 14.2 kg)
Did not use botanical dietary supplements or non-prescription/prescription medications aside from oral contraception in the female group, which they continued.
All females had a negative prenancy test at baseline
2 hours
Drug or Natural Product Administration
Oral
not specified
250 mg
once
twice in 28 day trial
Oral
capsule
2700 mg
three times daily
28 days
Wild Oats Markets, Inc. Boulder, CO.)
not specified
Pharmacodynamics (PD) & Adverse Events
Headache and Nausea