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1.
Drugs R D ; 14(2): 139-45, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24903027

RESUMO

Head and neck squamous cell cancer accounts for 3 % of new cancer cases and 2 % of cancer mortality annually in the United States. Current treatment options for most head and neck cancers continue to be surgical excision with or without radiation, radiation alone, or chemotherapy with radiation depending on location, stage of disease, and patient preference. Fusaric acid (FA) is a novel compound from a novel class of nicotinic acid derivatives that have activity against head and neck squamous cell carcinoma (HNSCC). Although its exact mechanism is still unknown, FA is thought to be active by increasing damage to DNA and preventing its synthesis and repair. The novel mechanism of FA provides an alternative to present therapies, as a single agent whether given parenterally or orally. It has synergy with conventional agents taxol, carboplatin, and erlotinib. In order to determine if FA has reasonable oral bioavailability, we have determined the pharmacokinetics of FA in male Sprague Dawley rats following administration by gavage and by intravenous injection. The bioavailability of FA was sufficient (58 %) to suggest that FA may be viable as an orally administered medication. Despite the encouraging bioavailability of FA, the intravenous (IV) pharmacokinetics suggested non-linear behavior within the IV dose range of 10, 25, and 75 mg/kg. These results demonstrate that further pharmacokinetic and toxicity studies in larger animals such as dogs and non-human primates are warranted.


Assuntos
Ácido Fusárico/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Cromatografia Líquida , Relação Dose-Resposta a Droga , Ácido Fusárico/administração & dosagem , Ácido Fusárico/sangue , Injeções Intravenosas , Masculino , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
2.
J Pharm Biomed Anal ; 49(4): 1021-6, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19269122

RESUMO

A high throughput liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of berberine and hydrastine in human serum, after oral administration of goldenseal (Hydrastis canadensis L.), was developed using simple acetonitrile treatment of serum samples. Noscapine served as the internal standard. Lower limit of quantification for both analytes was 0.1 ng mL(-1) using positive ion electrospray tandem mass spectrometry (MS/MS). The intra-day (n=5) accuracy and precision of the method for hydrastine was 82+/-8.8%, 97.9+/-2.4% and 96.2+/-3.3%, respectively. The inter-day (n=4) accuracy and precision for hydrastine was 90.0+/-15.17%, 99.9+/-7.1% and 98+/-6.54%, respectively. For berberine quantitation intra-day accuracy and precision was 96.0+/-8.4%, 92.5+/-4.7% and 94.4+/-3.7%, respectively. The respective values for inter-day quantitation were 91.0+/-8.4%, 94.3+/-4.7% and 94.4+/-3.7%. The analytical recovery for hydrastine was 82.4-96.2% and for berberine it was 94.4-96.0%. The analytes and noscapine were stable for 24h at room temperature (CV 5-10%). Matrix ion effects were studied by post-column infusion of hydrastine and berberine, calculation of calibration curve slope precision was obtained using serum from five different subjects, and by comparison of the response of methanol standards and extracted serum samples. The method was further validated by determination of serum pharmacokinetics of hydrastine and berberine after administration of a single oral dose of goldenseal extract containing 77 mg of hydrastine and 132 mg of berberine.


Assuntos
Benzilisoquinolinas/sangue , Berberina/sangue , Benzilisoquinolinas/farmacocinética , Berberina/farmacocinética , Calibragem , Cromatografia Líquida de Alta Pressão , Suplementos Nutricionais/análise , Humanos , Indicadores e Reagentes , Controle de Qualidade , Reprodutibilidade dos Testes , Solventes , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
3.
Mol Nutr Food Res ; 52(7): 755-63, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18214849

RESUMO

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.


Assuntos
Citocromo P-450 CYP2D6/metabolismo , Interações Ervas-Drogas , Hydrastis/efeitos adversos , Fitoterapia , Extratos Vegetais/farmacologia , Cimicifuga/metabolismo , Suplementos Nutricionais , Echinacea/metabolismo , Humanos , Hydrastis/metabolismo , Hypericum/metabolismo , Kava/metabolismo , Silybum marianum/metabolismo
4.
Drug Metab Dispos ; 35(2): 240-5, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17079360

RESUMO

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.


Assuntos
Cardiotônicos/farmacocinética , Digoxina/farmacocinética , Interações Ervas-Drogas , Hydrastis , Kava , Adulto , Claritromicina/farmacologia , Inibidores do Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Interações Medicamentosas , Feminino , Humanos , Masculino , Rifampina/farmacologia
5.
J Clin Pharmacol ; 46(2): 201-13, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16432272

RESUMO

Phytochemical-mediated modulation of cytochrome P450 enzymes (CYPs) may underlie many herb-drug interactions. This study's purpose was to assess the effects of milk thistle and black cohosh supplementation on CYP3A activity and compare them to a clinically recognized inducer, rifampin, and inhibitor, clarithromycin. Healthy volunteers were randomly assigned to receive a standardized milk thistle (900 mg) or black cohosh (80 mg) supplement for 14 days. Subjects also received rifampin (600 mg) and clarithromycin (1000 mg) for 7 days as positive controls for CYP3A induction and inhibition, respectively. Midazolam was administered orally before and after each supplementation and control period. The effects of milk thistle, black cohosh, rifampin, and clarithromycin on midazolam pharmacokinetics were determined using noncompartmental techniques. Unlike those observed for rifampin and clarithromycin, midazolam pharmacokinetics was unaffected by milk thistle or black cohosh. Milk thistle and black cohosh appear to have no clinically relevant effect on CYP3A activity in vivo.


Assuntos
Antibacterianos/farmacologia , Antibióticos Antituberculose/farmacologia , Cimicifuga/química , Claritromicina/farmacologia , Citocromo P-450 CYP3A/metabolismo , Suplementos Nutricionais , Rifampina/farmacologia , Silybum marianum/química , Adulto , Área Sob a Curva , Citocromo P-450 CYP3A/biossíntese , Inibidores do Citocromo P-450 CYP3A , Interações Medicamentosas , Ativadores de Enzimas/farmacologia , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Hipnóticos e Sedativos/farmacocinética , Masculino , Midazolam/farmacocinética , Fenótipo , Caracteres Sexuais
6.
Drug Metab Dispos ; 34(1): 69-74, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16221754

RESUMO

Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may underlie many herb-drug interactions. Serial serum concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with milk thistle or black cohosh modified P-gp activity in vivo. Sixteen healthy volunteers were randomly assigned to receive a standardized milk thistle (900 mg daily) or black cohosh (40 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 (Lanoxicaps, 0.4 mg) was administered orally before and at the end of each supplementation and control period. Serial digoxin serum concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the serum concentration time curves from 0 to 3 h (AUC(0-3)), AUC(0-24), Cmax, apparent oral clearance of digoxin (CL/F), and elimination half-life were used to assess the effects of milk thistle, black cohosh, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC(0-3), AUC(0-24), and Cmax, whereas clarithromycin increased these parameters significantly (p < 0.01). Significant changes in digoxin half-life and CL/F were also observed with clarithromycin. No statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either milk thistle or black cohosh, although digoxin AUC(0-3) and AUC(0-24) approached significance (p = 0.06) following milk thistle administration. When compared with rifampin and clarithromycin, supplementation with these specific formulations of milk thistle or black cohosh did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.


Assuntos
Cimicifuga , Digoxina/farmacocinética , Preparações de Plantas/farmacologia , Silybum marianum , Administração Oral , Adulto , Área Sob a Curva , Claritromicina/administração & dosagem , Claritromicina/farmacocinética , Suplementos Nutricionais , Digoxina/antagonistas & inibidores , Digoxina/sangue , Esquema de Medicação , Feminino , Genes MDR/genética , Meia-Vida , Haplótipos/genética , Interações Ervas-Drogas , Humanos , Masculino , Preparações de Plantas/administração & dosagem , Rifampina/administração & dosagem , Rifampina/farmacocinética , Rifampina/urina
7.
Drugs Aging ; 22(6): 525-39, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15974642

RESUMO

OBJECTIVES: 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.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Suplementos Nutricionais , Preparações de Plantas/farmacologia , Administração Oral , Idoso , Compostos Alílicos/química , Cafeína/administração & dosagem , Cafeína/sangue , Cafeína/farmacologia , Clorzoxazona/administração & dosagem , Clorzoxazona/sangue , Clorzoxazona/farmacologia , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/genética , Esquema de Medicação , Feminino , Ginkgo biloba/química , Interações Ervas-Drogas , Humanos , Hypericum/química , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Midazolam/administração & dosagem , Midazolam/sangue , Midazolam/farmacologia , Panax/química , Fenótipo , Preparações de Plantas/administração & dosagem , Preparações de Plantas/química , Sulfetos/química
8.
Clin Pharmacol Ther ; 77(5): 415-26, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15900287

RESUMO

OBJECTIVES: 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 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 women) 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 debrisoquin (INN, debrisoquine), were administered before (baseline) and at the end of supplementation. Presupplementation and postsupplementation phenotypic trait measurements were determined for CYP3A4/5, CYP1A2, CYP2E1, and CYP2D6 by 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. The content of purported "active" phytochemicals was determined for each supplement. RESULTS: Comparisons of presupplementation and postsupplementation phenotypic ratio means revealed significant inhibition (approximately 40%) of CYP2D6 (difference, -0.228; 95% confidence interval [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 (approximately 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 (approximately 7%) did not appear to be 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, whereas 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 to be less likely to produce CYP-mediated herb-drug interactions.


Assuntos
Hidrocarboneto de Aril Hidroxilases/efeitos dos fármacos , Hidrocarboneto de Aril Hidroxilases/genética , Cimicifuga/metabolismo , Hydrastis/metabolismo , Kava/metabolismo , Fenótipo , Valeriana/química , Adulto , Cafeína/farmacologia , Cápsulas , Cimicifuga/química , Suplementos Nutricionais , Esquema de Medicação , Feminino , Interações Ervas-Drogas/fisiologia , Humanos , Hydrastis/química , Kava/química , Masculino , Midazolam/farmacologia , Seleção de Pacientes , Fatores de Tempo , Valeriana/metabolismo
9.
Clin Pharmacol Ther ; 76(5): 428-40, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15536458

RESUMO

OBJECTIVES: 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 Citrus aurantium , Echinacea purpurea , milk thistle (Silybum marianum), or saw palmetto (Serenoa repens) extracts affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity. METHODS: Twelve healthy volunteers (6 women, 6 men) were randomly assigned to receive C aurantium , E purpurea , milk thistle, or saw palmetto 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 debrisoquin (INN, debrisoquine), were administered before (baseline) and at the end of supplementation. Presupplementation and postsupplementation phenotypic trait measurements were determined for CYP3A4, CYP1A2, CYP2E1, and CYP2D6 by 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. The content of purported "active" phytochemicals was determined for each supplement. RESULTS: Comparisons of presupplementation and postsupplementation phenotypic ratios suggested that these particular supplements had no significant effect on CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity. Phytochemical profiles indicated that C aurantium was devoid of the CYP3A4 inhibitor 6',7'-dihydroxybergamottin. Quantities of fatty acids, flavonolignans, and cichoric acid were consistent with label claims for saw palmetto, milk thistle, and E purpurea , respectively. CONCLUSIONS: Botanical supplements containing C aurantium , milk thistle, or saw palmetto extracts appear to pose a minimal risk for CYP-mediated herb-drug interactions in humans. Although the effects of E purpurea on CYP activity were minor, further study into the interaction potential of this botanical is merited.


Assuntos
Citrus/química , Sistema Enzimático do Citocromo P-450/metabolismo , Echinacea/química , Extratos Vegetais/química , Silybum marianum/química , Adrenérgicos/farmacocinética , Adulto , Cafeína/farmacocinética , Estimulantes do Sistema Nervoso Central/farmacocinética , Cromatografia Líquida de Alta Pressão , Debrisoquina/farmacocinética , Suplementos Nutricionais , Interações Medicamentosas , Feminino , Moduladores GABAérgicos/farmacocinética , Humanos , Isoenzimas/metabolismo , Cinética , Masculino , Midazolam/farmacocinética , Fenótipo , Extratos Vegetais/administração & dosagem , Serenoa , Solubilidade
10.
Clin Pharmacol Ther ; 72(3): 276-87, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12235448

RESUMO

OBJECTIVES: 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.


Assuntos
Citocromo P-450 CYP2E1/genética , Sistema Enzimático do Citocromo P-450/genética , Oxigenases de Função Mista/genética , Preparações de Plantas/administração & dosagem , Adulto , Compostos Alílicos/farmacocinética , Análise de Variância , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas/genética , Feminino , Ginkgo biloba/metabolismo , Interações Ervas-Drogas , Humanos , Hypericum/metabolismo , Masculino , Oxigenases de Função Mista/metabolismo , Panax/metabolismo , Fenótipo , Fitoterapia/métodos , Preparações de Plantas/farmacocinética , Valor Preditivo dos Testes , Fatores Sexuais , Sulfetos/farmacocinética
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