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Bill J Gurley - One of the best experts on this subject based on the ideXlab platform.
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Hydrastine pharmacokinetics and metabolism after a single oral dose of Goldenseal (Hydrastis canadensis) to humans.
Drug metabolism and disposition: the biological fate of chemicals, 2015Co-Authors: Prem K. Gupta, Bill J Gurley, Gary W. Barone, E. Kim Fifer, Howard P. HendricksonAbstract:The disposition and metabolism of hydrastine was investigated in 11 healthy subjects following an oral dose of 2.7 g of Goldenseal supplement containing 78 mg of hydrastine. Serial blood samples were collected for 48 hours, and urine was collected for 24 hours. Hydrastine serum and urine concentrations were determined by Liquid Chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters for hydrastine were calculated using noncompartmental methods. The maximal serum concentration ( C max ) was 225 ± 100 ng/ml, T max was 1.5 ± 0.3 hours, and area under the curve was 6.4 ± 4.1 ng⋅h/ml⋅kg. The elimination half-life was 4.8 ± 1.4 hours. Metabolites of hydrastine were identified in serum and urine by using liquid chromatography coupled to high-resolution mass spectrometry. Hydrastine metabolites were identified by various mass spectrometric techniques, such as accurate mass measurement, neutral loss scanning, and product ion scanning using Quadrupole-Time of Flight (Q-ToF) and triple quadrupole instruments. The identity of phase II metabolites was further confirmed by hydrolysis of glucuronide and sulfate conjugates using bovine β -glucuronidase and a Helix pomatia sulfatase/glucuronidase enzyme preparation. Hydrastine was found to undergo rapid and extensive phase I and phase II metabolism. Reduction, O -demethylation, N -demethylation, hydroxylation, aromatization, lactone hydrolysis, and dehydrogenation of the alcohol group formed by lactone hydrolysis to the ketone group were observed during phase I biotransformation of hydrastine. Phase II metabolites were primarily glucuronide and sulfate conjugates. Hydrastine undergoes extensive biotransformation, and some metabolites may have pharmacological activity. Further study is needed in this area.
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clinical assessment of cyp2d6 mediated herb drug interactions in humans effects of milk thistle black cohosh Goldenseal kava kava st john s wort and echinacea
Molecular Nutrition & Food Research, 2008Co-Authors: Bill J Gurley, Martha A Hubbard, Keith D Williams, Gary W. Barone, Ashley Swain, F Hartsfield, Yudong Tong, Danielle Julie Carrier, Shreekar Cheboyina, Sunil Kumar BattuAbstract:Cytochrome P450 2D6 (CYP2D6), an important CYP isoform with regard to drug-drug interactions, accounts for the metabolism of approximately 30% of all medications. To date, few studies have assessed the effects of botanical supplementation on human CYP2D6 activity in vivo. Six botanical extracts were evaluated in three separate studies (two extracts per study), each incorporating 16 healthy volunteers (eight females). Subjects were randomized to receive a standardized botanical extract for 14 days on separate occasions. A 30-day washout period was interposed between each supplementation phase. In study 1, subjects received milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa). In study 2, kava kava (Piper methysticum) and Goldenseal (Hydrastis canadensis) extracts were administered, and in study 3 subjects received St. John's wort (Hypericum perforatum) and Echinacea (Echinacea purpurea). The CYP2D6 substrate, debrisoquine (5 mg), was administered before and at the end of supplementation. Pre- and post-supplementation phenotypic trait measurements were determined for CYP2D6 using 8-h debrisoquine urinary recovery ratios (DURR). Comparisons of pre- and post-supplementation DURR revealed significant inhibition (approximately 50%) of CYP2D6 activity for Goldenseal, but not for the other extracts. Accordingly, adverse herb-drug interactions may result with concomitant ingestion of Goldenseal supplements and drugs that are CYP2D6 substrates.
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Supplementation with Goldenseal (Hydrastis canadensis), but not kava kava (Piper methysticum), inhibits human CYP3A activity in vivo
Clinical pharmacology and therapeutics, 2007Co-Authors: Bill J Gurley, Martha A Hubbard, Ashley Swain, F Hartsfield, John J. Thaden, David K. Williams, W.b. Gentry, Yudong TongAbstract:The effects of Goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on human CYP3A activity were evaluated using midazolam (MDZ) as a phenotypic probe. Sixteen healthy volunteers were randomly assigned to receive either Goldenseal or kava kava for 14 days. Each supplementation phase was followed by a 30-day washout period. MDZ (8 mg, per os) was administered before and after each phase, and pharmacokinetic parameters were determined using standard non-compartmental methods. Comparisons of pre- and post-supplementation MDZ pharmacokinetic parameters revealed significant inhibition of CYP3A by Goldenseal (AUC(0-infinity), 107.9+/-43.3 vs 175.3+/-74.8 ng x h/ml; Cl/F/kg, 1.26+/-0.59 vs 0.81+/-0.45 l/h/kg; T(1/2), 2.01+/-0.42 vs 3.15+/-1.12 h; Cmax, 50.6+/-26.9 vs 71.2+/-50.5 ng/ml). MDZ disposition was not affected by kava kava supplementation. These findings suggest that significant herb-drug interactions may result from the concomitant ingestion of Goldenseal and CYP3A substrates.
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effect of Goldenseal hydrastis canadensis and kava kava piper methysticum supplementation on digoxin pharmacokinetics in humans
Drug Metabolism and Disposition, 2007Co-Authors: Bill J Gurley, Martha A Hubbard, Keith D Williams, Gary W. Barone, Ashley Swain, Yudong Tong, Philip J Breen, Ryan C Yates, Leslie Stuart, Sreekhar CheboyinaAbstract:Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may give rise to many herb-drug interactions. Serial plasma concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with Goldenseal or kava kava modified P-gp activity in vivo. Twenty healthy volunteers were randomly assigned to receive a standardized Goldenseal (3210 mg daily) or kava kava (1227 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin, 0.5 mg) was administered p.o. before and at the end of each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC)((0-3)), AUC((0-24)), C(max,) CL/F, and elimination half-life were used to assess the effects of Goldenseal, kava kava, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC((0-3)), AUC((0-24)), CL/F, t(1/2), and C(max), whereas clarithromycin increased these parameters significantly (p < 0.01). With the exception of Goldenseal's effect on C(max) (14% increase), no statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either Goldenseal or kava kava. When compared with rifampin and clarithromycin, supplementation with these specific formulations of Goldenseal or kava kava did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.
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in vivo effects of Goldenseal kava kava black cohosh and valerian on human cytochrome p450 1a2 2d6 2e1 and 3a4 5 phenotypes
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Bill J Gurley, Stephanie F Gardner, Martha A Hubbard, Keith D Williams, Brooks W GentryAbstract: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.
Martha A Hubbard - One of the best experts on this subject based on the ideXlab platform.
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clinical assessment of cyp2d6 mediated herb drug interactions in humans effects of milk thistle black cohosh Goldenseal kava kava st john s wort and echinacea
Molecular Nutrition & Food Research, 2008Co-Authors: Bill J Gurley, Martha A Hubbard, Keith D Williams, Gary W. Barone, Ashley Swain, F Hartsfield, Yudong Tong, Danielle Julie Carrier, Shreekar Cheboyina, Sunil Kumar BattuAbstract:Cytochrome P450 2D6 (CYP2D6), an important CYP isoform with regard to drug-drug interactions, accounts for the metabolism of approximately 30% of all medications. To date, few studies have assessed the effects of botanical supplementation on human CYP2D6 activity in vivo. Six botanical extracts were evaluated in three separate studies (two extracts per study), each incorporating 16 healthy volunteers (eight females). Subjects were randomized to receive a standardized botanical extract for 14 days on separate occasions. A 30-day washout period was interposed between each supplementation phase. In study 1, subjects received milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa). In study 2, kava kava (Piper methysticum) and Goldenseal (Hydrastis canadensis) extracts were administered, and in study 3 subjects received St. John's wort (Hypericum perforatum) and Echinacea (Echinacea purpurea). The CYP2D6 substrate, debrisoquine (5 mg), was administered before and at the end of supplementation. Pre- and post-supplementation phenotypic trait measurements were determined for CYP2D6 using 8-h debrisoquine urinary recovery ratios (DURR). Comparisons of pre- and post-supplementation DURR revealed significant inhibition (approximately 50%) of CYP2D6 activity for Goldenseal, but not for the other extracts. Accordingly, adverse herb-drug interactions may result with concomitant ingestion of Goldenseal supplements and drugs that are CYP2D6 substrates.
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Supplementation with Goldenseal (Hydrastis canadensis), but not kava kava (Piper methysticum), inhibits human CYP3A activity in vivo
Clinical pharmacology and therapeutics, 2007Co-Authors: Bill J Gurley, Martha A Hubbard, Ashley Swain, F Hartsfield, John J. Thaden, David K. Williams, W.b. Gentry, Yudong TongAbstract:The effects of Goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on human CYP3A activity were evaluated using midazolam (MDZ) as a phenotypic probe. Sixteen healthy volunteers were randomly assigned to receive either Goldenseal or kava kava for 14 days. Each supplementation phase was followed by a 30-day washout period. MDZ (8 mg, per os) was administered before and after each phase, and pharmacokinetic parameters were determined using standard non-compartmental methods. Comparisons of pre- and post-supplementation MDZ pharmacokinetic parameters revealed significant inhibition of CYP3A by Goldenseal (AUC(0-infinity), 107.9+/-43.3 vs 175.3+/-74.8 ng x h/ml; Cl/F/kg, 1.26+/-0.59 vs 0.81+/-0.45 l/h/kg; T(1/2), 2.01+/-0.42 vs 3.15+/-1.12 h; Cmax, 50.6+/-26.9 vs 71.2+/-50.5 ng/ml). MDZ disposition was not affected by kava kava supplementation. These findings suggest that significant herb-drug interactions may result from the concomitant ingestion of Goldenseal and CYP3A substrates.
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effect of Goldenseal hydrastis canadensis and kava kava piper methysticum supplementation on digoxin pharmacokinetics in humans
Drug Metabolism and Disposition, 2007Co-Authors: Bill J Gurley, Martha A Hubbard, Keith D Williams, Gary W. Barone, Ashley Swain, Yudong Tong, Philip J Breen, Ryan C Yates, Leslie Stuart, Sreekhar CheboyinaAbstract:Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may give rise to many herb-drug interactions. Serial plasma concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with Goldenseal or kava kava modified P-gp activity in vivo. Twenty healthy volunteers were randomly assigned to receive a standardized Goldenseal (3210 mg daily) or kava kava (1227 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin, 0.5 mg) was administered p.o. before and at the end of each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC)((0-3)), AUC((0-24)), C(max,) CL/F, and elimination half-life were used to assess the effects of Goldenseal, kava kava, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC((0-3)), AUC((0-24)), CL/F, t(1/2), and C(max), whereas clarithromycin increased these parameters significantly (p < 0.01). With the exception of Goldenseal's effect on C(max) (14% increase), no statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either Goldenseal or kava kava. When compared with rifampin and clarithromycin, supplementation with these specific formulations of Goldenseal or kava kava did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.
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in vivo effects of Goldenseal kava kava black cohosh and valerian on human cytochrome p450 1a2 2d6 2e1 and 3a4 5 phenotypes
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Bill J Gurley, Stephanie F Gardner, Martha A Hubbard, Keith D Williams, Brooks W GentryAbstract: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.
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effect of Goldenseal black cohosh kava kava and valerian on human cytochrome p450 1a2 2d6 2e1 and 3a4 phenotypes
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Bill J Gurley, Stephanie F Gardner, Martha A Hubbard, David K. Williams, W.b. Gentry, I Khan, A ShahAbstract:Background Phytochemical-mediated modulation of cytochrome P450 activity may underlie many herb-drug interactions. Single time-point, phenotypic metabolic ratios were used to determine whether supplementation of Goldenseal, black cohosh, kava, or valerian extracts affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity. Methods Twelve healthy volunteers were randomly assigned to receive each 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-hr), paraxanthine/caffeine serum ratios (6-hr), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hr), and debrisoquine urinary recovery ratios (8-hr), respectively. Results Comparisons of pre- and post-Goldenseal phenotypic ratios revealed significant inhibition (~40%) of CYP2D6 and CYP3A4 activity. Black cohosh also inhibited CYP2D6, but the magnitude (~7%) did not appear clinically relevant. No significant changes were observed for kava or valerian. Conclusions Goldenseal strongly inhibited CYP2D6 and CYP3A4 activity. Accordingly, serious adverse interactions may result if Goldenseal is ingested with drugs that are CYP2D6 and CYP3A4 substrates. Kava, black cohosh and valerian appear less likely to produce such interactions. Clinical Pharmacology & Therapeutics (2005) 77, P36–P36; doi: 10.1016/j.clpt.2004.12.030
Brooks W Gentry - One of the best experts on this subject based on the ideXlab platform.
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in vivo effects of Goldenseal kava kava black cohosh and valerian on human cytochrome p450 1a2 2d6 2e1 and 3a4 5 phenotypes
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Bill J Gurley, Stephanie F Gardner, Martha A Hubbard, Keith D Williams, Brooks W GentryAbstract: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.
Keith D Williams - One of the best experts on this subject based on the ideXlab platform.
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clinical assessment of cyp2d6 mediated herb drug interactions in humans effects of milk thistle black cohosh Goldenseal kava kava st john s wort and echinacea
Molecular Nutrition & Food Research, 2008Co-Authors: Bill J Gurley, Martha A Hubbard, Keith D Williams, Gary W. Barone, Ashley Swain, F Hartsfield, Yudong Tong, Danielle Julie Carrier, Shreekar Cheboyina, Sunil Kumar BattuAbstract:Cytochrome P450 2D6 (CYP2D6), an important CYP isoform with regard to drug-drug interactions, accounts for the metabolism of approximately 30% of all medications. To date, few studies have assessed the effects of botanical supplementation on human CYP2D6 activity in vivo. Six botanical extracts were evaluated in three separate studies (two extracts per study), each incorporating 16 healthy volunteers (eight females). Subjects were randomized to receive a standardized botanical extract for 14 days on separate occasions. A 30-day washout period was interposed between each supplementation phase. In study 1, subjects received milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa). In study 2, kava kava (Piper methysticum) and Goldenseal (Hydrastis canadensis) extracts were administered, and in study 3 subjects received St. John's wort (Hypericum perforatum) and Echinacea (Echinacea purpurea). The CYP2D6 substrate, debrisoquine (5 mg), was administered before and at the end of supplementation. Pre- and post-supplementation phenotypic trait measurements were determined for CYP2D6 using 8-h debrisoquine urinary recovery ratios (DURR). Comparisons of pre- and post-supplementation DURR revealed significant inhibition (approximately 50%) of CYP2D6 activity for Goldenseal, but not for the other extracts. Accordingly, adverse herb-drug interactions may result with concomitant ingestion of Goldenseal supplements and drugs that are CYP2D6 substrates.
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effect of Goldenseal hydrastis canadensis and kava kava piper methysticum supplementation on digoxin pharmacokinetics in humans
Drug Metabolism and Disposition, 2007Co-Authors: Bill J Gurley, Martha A Hubbard, Keith D Williams, Gary W. Barone, Ashley Swain, Yudong Tong, Philip J Breen, Ryan C Yates, Leslie Stuart, Sreekhar CheboyinaAbstract:Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may give rise to many herb-drug interactions. Serial plasma concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with Goldenseal or kava kava modified P-gp activity in vivo. Twenty healthy volunteers were randomly assigned to receive a standardized Goldenseal (3210 mg daily) or kava kava (1227 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin, 0.5 mg) was administered p.o. before and at the end of each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC)((0-3)), AUC((0-24)), C(max,) CL/F, and elimination half-life were used to assess the effects of Goldenseal, kava kava, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC((0-3)), AUC((0-24)), CL/F, t(1/2), and C(max), whereas clarithromycin increased these parameters significantly (p < 0.01). With the exception of Goldenseal's effect on C(max) (14% increase), no statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either Goldenseal or kava kava. When compared with rifampin and clarithromycin, supplementation with these specific formulations of Goldenseal or kava kava did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.
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in vivo effects of Goldenseal kava kava black cohosh and valerian on human cytochrome p450 1a2 2d6 2e1 and 3a4 5 phenotypes
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Bill J Gurley, Stephanie F Gardner, Martha A Hubbard, Keith D Williams, Brooks W GentryAbstract: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.
Stephanie F Gardner - One of the best experts on this subject based on the ideXlab platform.
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in vivo effects of Goldenseal kava kava black cohosh and valerian on human cytochrome p450 1a2 2d6 2e1 and 3a4 5 phenotypes
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Bill J Gurley, Stephanie F Gardner, Martha A Hubbard, Keith D Williams, Brooks W GentryAbstract: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.
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effect of Goldenseal black cohosh kava kava and valerian on human cytochrome p450 1a2 2d6 2e1 and 3a4 phenotypes
Clinical Pharmacology & Therapeutics, 2005Co-Authors: Bill J Gurley, Stephanie F Gardner, Martha A Hubbard, David K. Williams, W.b. Gentry, I Khan, A ShahAbstract:Background Phytochemical-mediated modulation of cytochrome P450 activity may underlie many herb-drug interactions. Single time-point, phenotypic metabolic ratios were used to determine whether supplementation of Goldenseal, black cohosh, kava, or valerian extracts affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity. Methods Twelve healthy volunteers were randomly assigned to receive each 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-hr), paraxanthine/caffeine serum ratios (6-hr), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hr), and debrisoquine urinary recovery ratios (8-hr), respectively. Results Comparisons of pre- and post-Goldenseal phenotypic ratios revealed significant inhibition (~40%) of CYP2D6 and CYP3A4 activity. Black cohosh also inhibited CYP2D6, but the magnitude (~7%) did not appear clinically relevant. No significant changes were observed for kava or valerian. Conclusions Goldenseal strongly inhibited CYP2D6 and CYP3A4 activity. Accordingly, serious adverse interactions may result if Goldenseal is ingested with drugs that are CYP2D6 and CYP3A4 substrates. Kava, black cohosh and valerian appear less likely to produce such interactions. Clinical Pharmacology & Therapeutics (2005) 77, P36–P36; doi: 10.1016/j.clpt.2004.12.030