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1.
Food Chem Toxicol ; 153: 112278, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34019943

RESUMO

Bergamottin (BGM) is a major furanocoumarin constituent of grapefruit and is reported to have inhibitory effects on cytochrome P450 enzymes. This study investigated the chemical interactions between BGM and the enzyme CYP2C9. BGM exhibited time-, concentration-, and NADPH-dependent inhibition of CYP2C9. Co-incubation with diclofenac, a reversible inhibitor of CYP2C9, attenuated the time-dependent enzyme inhibition. Exhaustive dialysis did not restore enzyme activity post-inhibition. Glutathione (GSH) and catalase/superoxide dismutase failed to reverse BGM-induced CYP2C9 inactivation. A GSH trapping study suggested that BGM was metabolized to an epoxide and/or γ-ketoenal that may have been responsible for the enzyme inactivation. In conclusion, BGM can be characterized as a mechanism-based inactivator of CYP2C9 acting via the formation of an epoxide and/or γ-ketoenal.


Assuntos
Inibidores do Citocromo P-450 CYP2C9/farmacologia , Citocromo P-450 CYP2C9/metabolismo , Furocumarinas/farmacologia , Inibidores do Citocromo P-450 CYP2C9/metabolismo , Diclofenaco/farmacologia , Furocumarinas/metabolismo , Humanos , Microssomos Hepáticos/metabolismo
2.
Chem Biol Interact ; 343: 109498, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33961833

RESUMO

The drug-drug interaction (DDI) risk of phenytoin with several topical formulations of miconazole is still unclear. The present investigation conducted in vitro-in vivo extrapolation to predict the potential risks. Our data indicated that miconazole potently inhibited phenytoin hydroxylation in both pooled human liver microsomes (HLMs) and recombinant cytochrome P450 2C9 (CYP2C9) with the Ki values of 125 ± 7 nM and 30 ± 2 nM, respectively. Quantitative prediction of DDI risk suggests that, beside intravenous administration or swallowed tablet, combination of phenytoin and miconazole high dose oral gel or buccal tablet may also result in a clinically significant increase of phenytoin AUC (>53%) by the inhibition of miconazole against phenytoin hydroxylation, consequently a higher frequency of adverse events, while the coadministration of miconazole vaginal formulation and phenytoin will be safe.


Assuntos
Inibidores do Citocromo P-450 CYP2C9/farmacologia , Miconazol/farmacologia , Fenitoína/metabolismo , Anticonvulsivantes/metabolismo , Antifúngicos/farmacologia , Citocromo P-450 CYP2C9/química , Citocromo P-450 CYP2C9/metabolismo , Interações Medicamentosas , Humanos , Hidroxilação/efeitos dos fármacos , Cinética , Microssomos Hepáticos/metabolismo , Medição de Risco
3.
Pharm Biol ; 59(1): 532-536, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33915070

RESUMO

CONTEXT: Pogostone possesses various pharmacological activities, which makes it widely used in the clinic. Its effect on the activity of cytochrome P450 enzymes (CYP450s) could guide its clinical combination. OBJECTIVE: To investigate the effect of pogostone on the activity of human CYP450s. MATERIALS AND METHODS: The effect of pogostone on the activity of CYP450s was evaluated in human liver microsomes (HLMs) compared with blank HLMs (negative control) and specific inhibitors (positive control). The corresponding parameters were obtained with 0-100 µM pogostone and various concentrations of substrates. RESULTS: Pogostone was found to inhibit the activity of CYP3A4, 2C9, and 2E1 with the IC50 values of 11.41, 12.11, and 14.90 µM, respectively. The inhibition of CYP3A4 by pogostone was revealed to be performed in a non-competitive and time-dependent manner with the Ki value of 5.69 µM and the KI/Kinact value of 5.86/0.056/(µM/min). For the inhibition of CYP2C9 and 2E1, pogostone acted as a competitive inhibitor with the Ki value of 6.46 and 7.67 µM and was not affected by the incubation time. DISCUSSION AND CONCLUSIONS: The inhibitory effect of pogostone on the activity of CYP3A4, 2C9, and 2E1 has been disclosed in this study, implying the potential risk during the co-administration of pogostone and drugs metabolized by these CYP450s. The study design provides a reference for further in vivo investigations to validate the potential interaction.


Assuntos
Inibidores do Citocromo P-450 CYP2C9/farmacologia , Inibidores do Citocromo P-450 CYP2E1/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Óleos Voláteis/farmacologia , Citocromo P-450 CYP2C9/efeitos dos fármacos , Citocromo P-450 CYP2C9/metabolismo , Inibidores do Citocromo P-450 CYP2C9/administração & dosagem , Citocromo P-450 CYP2E1/efeitos dos fármacos , Citocromo P-450 CYP2E1/metabolismo , Inibidores do Citocromo P-450 CYP2E1/administração & dosagem , Citocromo P-450 CYP3A/efeitos dos fármacos , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Óleos Voláteis/administração & dosagem , Fatores de Tempo
4.
Bioorg Med Chem Lett ; 40: 127924, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33705901

RESUMO

In this study, a series of sulfonamide compounds was designed and synthesized through the systematic optimization of the antibacterial agent sulfaphenazole for the treatment of Mycobacterium tuberculosis (M. tuberculosis). Preliminary results indicate that the 4-aminobenzenesulfonamide moiety plays a key role in maintaining antimycobacterial activity. Compounds 10c, 10d, 10f and 10i through the optimization on phenyl ring at the R2 site on the pyrazole displayed promising antimycobacterial activity paired with low cytotoxicity. In particular, compound 10d displayed good activity (MIC = 5.69 µg/mL) with low inhibition of CYP 2C9 (IC50 > 10 µM), consequently low potential risk of drug-drug interaction. These promising results provide new insight into the combination regimen using sulfonamide as one component for the treatment of M. tuberculosis.


Assuntos
Antituberculosos/farmacologia , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Sulfafenazol/análogos & derivados , Sulfafenazol/farmacologia , Sulfonamidas/farmacologia , Antituberculosos/síntese química , Inibidores do Citocromo P-450 CYP2C9/síntese química , Desenho de Fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Relação Estrutura-Atividade , Sulfonamidas/síntese química
5.
Anticancer Res ; 41(3): 1357-1364, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33788727

RESUMO

BACKGROUND/AIM: Amentoflavone, an effective compound derived from medicinal plants, has been shown to boost therapeutic efficacy of chemotherapy in non-small cell lung cancer (NSCLC). However, anti-NSCLC effect of amentoflavone is ambiguous. The major purpose of the present study was to verify the inhibitory effects of amentoflavone in NSCLC cells. MATERIALS AND METHODS: The effects of amentoflavone on growth and invasion of NSCLC CL-1-5-F4 cells were evaluated by cell viability assay, flow cytometry, colony formation assay, nuclear factor-kappa B (NF-κB) reporter gene assay, immunofluorescence staining, transwell invasion, and western blot assay. RESULTS: Amentoflavone effectively induced cell growth inhibition, G1 cell-cycle arrest, apoptosis, and suppression of invasion. Furthermore, amentoflavone not only triggered expression of p27, cleaved caspase-3, -8 also reduced NF-κB signaling, protein levels of matrix metalloproteinase (MMP)-2, -9, Cyclin-D1, and vascular endothelial growth factor (VEGF). CONCLUSION: Cell-cycle arrest, apoptosis induction, NF-κB signaling inhibition are associated with amentoflavone-inhibited growth and invasion of NSCLC cells.


Assuntos
Apoptose/efeitos dos fármacos , Biflavonoides/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular , Humanos , Neoplasias Pulmonares/metabolismo , Metaloproteinases da Matriz/metabolismo , NF-kappa B/metabolismo , Invasividade Neoplásica , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
6.
Phytomedicine ; 81: 153416, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33321412

RESUMO

BACKGROUND: Bulbine natalensis is an African-folk medicinal plant used as a dietary supplement for enhancing sexual function and muscle strength in males by presumably boosting testosterone levels, but no scientific information is available about the possible herb-drug interaction (HDI) risk when bulbine-containing supplements are concomitantly taken with prescription drugs. PURPOSE: This study was aimed to investigate the HDI potential of B. natalensis in terms of the pregnane X receptor (PXR)-mediated induction of major drug-metabolizing cytochrome P450 enzyme isoforms (i.e., CYP3A4 and CYP2C9) as well as inhibition of their catalytic activity. RESULTS: We found that a methanolic extract of B. natalensis activated PXR (EC50 6.2 ± 0.6 µg/ml) in HepG2 cells resulting in increased mRNA expression of CYP3A4 (2.40 ± 0.01 fold) and CYP2C9 (3.37 ± 0.3 fold) at 30 µg/ml which was reflected in increased activites of the two enzymes. Among the constituents of B. natalensis, knipholone was the most potent PXR activator (EC50 0.3 ± 0.1 µM) followed by bulbine-knipholone (EC50 2.0 ± 0.5 µM), and 6'-methylknipholone (EC50 4.0 ± 0.5 µM). Knipholone was also the most effective in increasing the expression of CYP3A4 (8.47 ± 2.5 fold) and CYP2C9 (2.64 ± 0.3 fold) at 10 µM. Docking studies further confirmed the unique structural features associated with knipholones for their superior inductive potentials in the activation of PXR compared to other anthraquinones. In a CYP inhibition assay, the methanolic extract as well as the anthraquinones strongly inhibited the catalytic activity of CYP2C9 while, inhibition of CYP3A4 was weak. CONCLUSIONS: These results suggest that consumption of B. natalensis may pose a potential risk for HDI if taken with conventional medications that are substrates of CYP3A4 and CYP2C9 and may contribute to unanticipated adverse reactions or therapeutic failures. Further studies are warranted to validate these findings and establish their clinical relevancy.


Assuntos
Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Suplementos Nutricionais , Interações Ervas-Drogas , Xanthorrhoeaceae/química , Inibidores do Citocromo P-450 CYP2C9/química , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/farmacologia , Suplementos Nutricionais/efeitos adversos , Células Hep G2 , Humanos , Masculino , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Receptor de Pregnano X/química , Receptor de Pregnano X/genética , Receptor de Pregnano X/metabolismo
7.
Pharm Biol ; 58(1): 1150-1155, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33327821

RESUMO

CONTEXT: Succinic acid, extracted from amber, is widely used in cardiovascular therapy. OBJECTIVE: The effect of succinic acid on the activity of cytochrome P450 (CYP450) enzymes was investigated in this study. MATERIALS AND METHODS: The effect of succinic acid (100 µM) on the activity of eight isoforms of CYP450 (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8) was investigated compared to the specific inhibitor and blank controls in pooled human liver microsomes in vitro. The inhibition of CYPs was fitted with competitive or non-competitive inhibition models and corresponding parameters were also obtained. RESULTS: Succinic acid exerted inhibitory effect on the activity of CYP3A4, 2D6, and 2C9 with the IC50 values of 12.82, 14.53, and 19.60 µM, respectively. Succinic acid inhibited the activity of CYP3A4 in a non-competitive manner with the Ki value of 6.18 µM, and inhibited CYP2D6 and 2C9 competitively with Ki values of 7.40 and 9.48 µM, respectively. Furthermore, the inhibition of CYP3A4 was found to be time-dependent with the KI/Kinact value of 6.52/0.051 min-1·µM-1. DISCUSSION AND CONCLUSIONS: Succinic acid showed in vitro inhibitory effects on the activity of CYP3A4, 2D6, and 2C9, which indicated the potential drug-drug interactions. Succinic acid should be carefully co-administrated with the drugs metabolized by CYP3A4, 2D6, and 2C9.


Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Ácido Succínico/farmacologia , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Humanos , Cinética
8.
Bioorg Med Chem Lett ; 30(21): 127571, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32980515

RESUMO

NLRP3 inflammasome mediated release of interleukin-1ß (IL-1ß) has been implicated in various diseases, including COVID-19. In this study, rationally designed alkenyl sulfonylurea derivatives were identified as novel, potent and orally bioavailable NLRP3 inhibitors. Compound 7 was found to be potent (IL-1ß IC50 = 35 nM; IL-18 IC50 = 33 nM) and selective NLRP3 inflammasome inhibitor with excellent pharmacokinetic profile having oral bioavailability of 99% in mice.


Assuntos
Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Compostos de Sulfonilureia/farmacologia , Administração Oral , Animais , Betacoronavirus , COVID-19 , Linhagem Celular Tumoral , Infecções por Coronavirus , Inibidores do Citocromo P-450 CYP2C8/administração & dosagem , Inibidores do Citocromo P-450 CYP2C8/síntese química , Inibidores do Citocromo P-450 CYP2C8/farmacocinética , Inibidores do Citocromo P-450 CYP2C8/farmacologia , Inibidores do Citocromo P-450 CYP2C9/administração & dosagem , Inibidores do Citocromo P-450 CYP2C9/síntese química , Inibidores do Citocromo P-450 CYP2C9/farmacocinética , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Cães , Estabilidade de Medicamentos , Humanos , Interleucina-1beta/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Pandemias , Pneumonia Viral , Ratos , SARS-CoV-2 , Relação Estrutura-Atividade , Compostos de Sulfonilureia/administração & dosagem , Compostos de Sulfonilureia/síntese química , Compostos de Sulfonilureia/farmacocinética
9.
Drug Metab Rev ; 52(2): 235-257, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32406758

RESUMO

Due to the rapidly increasing global interest in the use of herbs, phytomedicines and other natural products as medical or complementary remedies, concerns about the clinical medication safety have drawn much attention worldwide. Particularly, many natural ingredients exhibit inhibitory effects on cytochrome P450 (CYP) enzymes, which are the most important Phase I metabolism enzymes in liver. CYP2C9 is one of the most abundant CYP enzymes and responsible for the metabolism of over 15% clinical drugs, including oral sulfonylurea hypoglycemics, nonsteroidal anti-inflammatory agents, selective cyclooxygenase-2 inhibitors, antiepileptics, angiotensin II receptor inhibitors and anticoagulants. Diclofenac (4'-hydroxylase) and tolbutamide (methylhydroxylation) are widely used as probe substrates for CYP2C9. To date, numerous natural products have been reported to have the capabilities of inhibiting the catalytic activity of CYP2C9 and further influencing the pharmacokinetic and pharmacodynamic behaviors of drugs that are mainly metabolized by CYP2C9, leading to potential herb-drug interactions. Moreover, some fatal adverse interactions may occur for drugs with a narrow therapeutic window when they are coadministered with a CYP2C9 inhibitor, especially irreversible inactivators. For the purpose of better understanding the interactions of natural products with CYP2C9, we comprehensively reviewed the characteristics of CYP2C9, the natural ingredients that inhibit CYP2C9, the related research approaches and strategies, the types of inhibition and the underlying mechanisms.


Assuntos
Produtos Biológicos/farmacologia , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Animais , Citocromo P-450 CYP2C9/metabolismo , Interações Ervas-Drogas , Humanos , Extratos Vegetais/farmacologia
10.
Front Biosci (Landmark Ed) ; 25: 798-816, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31585918

RESUMO

Previous studies have shown that amentoflavone (AF) elicits anti-inflammatory and neuroprotective effects. To further investigate the effects of AF on the microglia cell line BV-2, proteomic analysis was performed to screen potential key regulators. The top 5 canonical pathways associated with AF treatment were EIF2 signaling, regulation of eIF4 and p70s6k signaling, mTOR signaling, protein ubiquitination pathway and phagosome maturation. The top up-regulated genes were DOCK2, SEC23A, ME1, UGGT1 and STOM, while the most down-regulated molecules were IGF2R, ATP5O, DDX47, WBP11 and IKBIP. AF significantly decreased BV-2 cell proliferation. It induced cell cycle arrest at G2/M, increased CDK2, p27Kip1 and p53/p-p53, and decreased CDK1/CDC2 and cyclin B1. Cell apoptosis was induced, with increased levels of BAX, c-caspase-3 and c-caspase-9, and decreased levels of BCL-XL. Increased level of autophagosome induced by AF was observed, and increased Beclin-1 and decreased phosphorylation of PI3K and Erk1 were found as well. In conclusion, AF induces cell cycle arrest at G2/M, promotes apoptosis and autophagy in BV-2 cells, which may account for the anti-inflammatory effect of AF in epilepsy.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Biflavonoides/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Microglia/efeitos dos fármacos , Animais , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Relação Dose-Resposta a Droga , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Camundongos , Microglia/citologia , Microglia/metabolismo , Proteoma/metabolismo , Transdução de Sinais/efeitos dos fármacos
11.
Brain Behav ; 9(10): e01400, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31486271

RESUMO

BACKGROUND: Peripheral nerve injury (PNI) causes motor and sensory defects, has strong impact on life quality and still has no effective therapy. Miconazole is one of the most widely used antifungal drugs; the aims of the study were to investigate the effects of miconazole during sciatic nerve regeneration in a mouse model of sciatic nerve crush injury. METHODS: We established peripheral nerve crush model and investigated the effects of miconazole by multiple aspects. We further studied the potential mechanism of action of miconazole by Western blotting, fluorescence immunohistochemistry, and PCR analysis. RESULTS: Miconazole improves the symptoms of crushed nerve by improving inflammatory cell infiltration and demyelinating myelin of sciatic nerve. Affected by miconazole, the proportion of inflammatory M1 macrophages in the distal part of the sciatic nerve was reduced, and the proportion of anti-inflammatory M2 macrophages was increased. Finally, the neuroprotective properties of miconazole may be regulated by the nuclear factor (NF)-κB pathway. CONCLUSIONS: Our data suggest that miconazole can effectively alleviate PNI, and the mechanism involves mediating a phenotype change of M1/ M2 macrophages. Thus, miconazole may represent a potential therapeutic intervention for nerve crush injury.


Assuntos
Lesões por Esmagamento/tratamento farmacológico , Miconazol/farmacologia , NF-kappa B/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Animais , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Modelos Animais de Doenças , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Compressão Nervosa , Regeneração Nervosa/fisiologia , Fenótipo , Nervo Isquiático/lesões
12.
Clin Pharmacol Ther ; 106(5): 1113-1124, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31199498

RESUMO

We predicted the drug-drug interaction (DDI) potential of siponimod in presence of cytochrome P450 (CYP)2C9/CYP3A4 inhibitors/inducers in subjects with different CYP2C9 genotypes by physiologically-based pharmacokinetic (PK) modeling. The model was established using in vitro and clinical PK data and verified by adequately predicting siponimod PK when coadministered with rifampin. With strong and moderate CYP3A4 inhibitors, an increased DDI risk for siponimod was predicted for CYP2C9*3/*3 genotype vs. other genotypes area under the curve ratio (AUCR): 3.03-4.20 vs. ≤ 1.49 for strong; 2.42 vs. 1.14-1.30 for moderate. AUCRs increased with moderate (2.13-2.49) and weak (1.12-1.42) CYP3A4/CYP2C9 inhibitors to the same extent for all genotypes. With strong CYP3A4/moderate CYP2C9 inducers and moderate CYP3A4 inducers, predicted AUCRs were 0.21-0.32 and 0.35-0.71, respectively. This complementary analysis to the clinical PK-DDI studies confirmed the relevant influence of CYP2C9 polymorphism on the DDI behavior of siponimod and represented the basis for the DDI labeling recommendations.


Assuntos
Azetidinas/farmacocinética , Compostos de Benzil/farmacocinética , Indutores das Enzimas do Citocromo P-450/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Modelos Biológicos , Rifampina/farmacologia , Área Sob a Curva , Simulação por Computador , Citocromo P-450 CYP2C9/genética , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Indutores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações Medicamentosas , Genótipo , Meia-Vida , Humanos
13.
Basic Clin Pharmacol Toxicol ; 124(1): 28-31, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30326170

RESUMO

Delta-9-tetrahydrocannabinol (THC), the main psychoactive cannabinoid in cannabis, may inhibit the cytochrome P450 enzyme CYP2C9. Consequently, cannabis use might infer a risk of drug-drug interaction with substrates for this enzyme, which includes drugs known to have a narrow therapeutic window. In this study, we describe a case report of a 27-year-old man treated with warfarin due to mechanical heart valve replacement who presented with elevated international normalized ratio (INR) value (INR = 4.6) following recreational cannabis use. We conducted a review of the available literature, using the PubMed and EMBASE databases while following PRISMA guidelines. Following screening of 85 articles, three eligible articles were identified, including one in vitro study and two case reports. The in vitro study indicated that THC inhibits the CYP2C9-mediated metabolism of warfarin. One case study reported of a man who on two occasions of increased marijuana use experienced INR values above 10 as well as bleeding. The other case study reported of a patient who initiated treatment with a liquid formulation of cannabidiol for the management of epilepsy, ultimately necessitating a 30% reduction in warfarin dose to maintain therapeutic INR values. The available, although sparse, data suggest that use of cannabinoids increases INR values in patients receiving warfarin. Until further data are available, we suggest patients receiving warfarin be warned against cannabis use.


Assuntos
Anticoagulantes/farmacologia , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Dronabinol/farmacologia , Acidente Vascular Cerebral/prevenção & controle , Varfarina/farmacologia , Adulto , Anticoagulantes/uso terapêutico , Cannabis/química , Citocromo P-450 CYP2C9/metabolismo , Interações Medicamentosas , Endocardite/cirurgia , Implante de Prótese de Valva Cardíaca/efeitos adversos , Humanos , Coeficiente Internacional Normatizado , Masculino , Fumar Maconha/efeitos adversos , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/etiologia , Transtornos Relacionados ao Uso de Substâncias/complicações , Varfarina/uso terapêutico
14.
Eur J Drug Metab Pharmacokinet ; 44(3): 423-431, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30306496

RESUMO

BACKGROUND AND OBJECTIVE: A significant number of people worldwide consume khat on daily basis. Long term of khat chewing has shown negative impact on several organ systems. It is likely that these people are co-administered khat preparations and conventional medication, which may lead to khat-drug interactions. This study aimed to reveal the inhibitory potencies of khat ethanol extract (KEE) and its major active ingredient (cathinone) on human cytochrome P450 (CYP) 2C9, CYP2D6, and CYP3A4 enzymes activities, which are collectively responsible for metabolizing 70-80% clinically used drugs. METHODS: In vitro fluorescence-based enzyme assays were developed and the CYP enzyme activities were quantified in the presence and absence of KEE and cathinone employing Vivid® CYP450 Screening Kits. RESULTS: KEE inhibited human CYP2C9, CYP2D6, and CYP3A4 enzyme activities with IC50 of 42, 62, and 18 µg/ml. On the other hand, cathinone showed negligible inhibitory effect on these CYPs. Further experiments with KEE revealed that KEE inhibited CYP2C9 via non-competitive or mixed mode with Ki of 14.7 µg/ml, CYP2D6 through competitive or mixed mode with Ki of 17.6 µg/ml, CYP3A4 by mixed inhibition mode with Ki of 12.1 µg/ml. CONCLUSION: Khat-drug interactions are possible due to administration of clinical drugs metabolized by CYP2C9/CYP2D6/CYP3A4 together with khat chewing. Further in vivo studies are required to confirm our findings and identify the causative constituents of these inhibitory effects.


Assuntos
Alcaloides/farmacologia , Catha/química , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Extratos Vegetais/farmacologia , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Etanol/química , Humanos , Proteínas Recombinantes/metabolismo , Solventes/química
15.
J Med Chem ; 61(24): 11074-11100, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30384606

RESUMO

A HTS campaign identified compound 1, an excellent hit-like molecule to initiate medicinal chemistry efforts to optimize a dual ROCK1 and ROCK2 inhibitor. Substitution (2-Cl, 2-NH2, 2-F, 3-F) of the pyridine hinge binding motif or replacement with pyrimidine afforded compounds with a clean CYP inhibition profile. Cocrystal structures of an early lead compound were obtained in PKA, ROCK1, and ROCK2. This provided critical structural information for medicinal chemistry to drive compound design. The structural data indicated the preferred configuration at the central benzylic carbon would be ( R), and application of this information to compound design resulted in compound 16. This compound was shown to be a potent and selective dual ROCK inhibitor in both enzyme and cell assays and efficacious in the retinal nerve fiber layer model after oral dosing. This tool compound has been made available through the AbbVie Compound Toolbox. Finally, the cocrystal structures also identified that aspartic acid residues 176 and 218 in ROCK2, which are glutamic acids in PKA, could be targeted as residues to drive both potency and kinome selectivity. Introduction of a piperidin-3-ylmethanamine group to the compound series resulted in compound 58, a potent and selective dual ROCK inhibitor with excellent predicted drug-like properties.


Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Inibidores do Citocromo P-450 CYP2C9/química , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Meia-Vida , Humanos , Camundongos Endogâmicos C57BL , Traumatismos do Nervo Óptico/tratamento farmacológico , Traumatismos do Nervo Óptico/patologia , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Quinases Associadas a rho/química
16.
J Pharm Biomed Anal ; 160: 195-201, 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30099291

RESUMO

The aim of this article is to assess the effect of phthalates on the activities of CYP2C9 and CYP2C19 in vitro. In this study, recombinant CYP2C9*1 and CYP2C19*1 microsomes were used to investigate the effects of phthalates and their metabolites on corresponding enzyme activities in vitro. 2-100 µM substrate of enzyme was incubated with series concentration of phthalates for 30 min at 37 °C. The metabolic products were detected using ultra-high performance liquid chromatography (UHPLC) and ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) methods. The results showed dibutyl phthalate (DBP) significantly inhibited CYP2C9*1 with an activity inhibition rate of 67.3% and half-maximal inhibitory concentration (IC50) of 29.63 µmol L-1, but its metabolite monobutyl phthalate (MBP) had no significant effect. On the other hand, di(2-ethylhexyl)phthalate (DEHP) had no effect on CYP2C9*1, but its metabolite monoethylhexyl phthalate (MEHP) significantly inhibited the enzyme activity with an activity inhibition rate of 90.6% and IC50 of 6.37 µmol L-1. With regards to CYP2C19*1, DBP completely inhibited the enzyme activity with an activity inhibition rate of 100% and IC50 of 2.63 µmol L-1, but its metabolite MBP had no effect on it. DEHP and MEHP also inhibited the activity of CYP2C19*1. Further investigation showed MEHP was a competitive inhibitor of CYP2C9*1 (Ki = 7.063 µmol L-1), and DBP was a competitive inhibitor of CYP2C19*1 (Ki = 7.013 µmol L-1) against their substrates, both phthalates were non-competitive inhibitors of the cofactor NADPH. Our results suggested that DBP, DEHP, and their metabolites exhibited significant inhibitory effects toward either CYP2C9*1 or CYP2C19*1. These findings provided valuable information for a potentially toxic mechanism of DEHP and DBP on endocrine disruption and a useful guidance for safe and effective usage of drugs in patients with long-term DEHP and DBP exposure.


Assuntos
Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Dibutilftalato/farmacologia , Dietilexilftalato/farmacologia , Inibidores do Citocromo P-450 CYP2C19/farmacologia , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Humanos , Concentração Inibidora 50 , Microssomos/metabolismo , Ácidos Ftálicos/farmacologia
17.
Biomed Pharmacother ; 107: 777-784, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30142539

RESUMO

Polyphenols are abundant molecules in the plant kingdom. They interact with several proteins in the body resulting in their complex biological effects. Previous studies demonstrated that polyphenols can interfere significantly with the pharmacokinetics of drugs by acting on their biotransformation, albumin-binding, and/or carrier-mediated transport. Casticin (CAS), ipriflavone (IPR), and resveratrol (RES) are well-known polyphenols often added to dietary supplements in high doses. In this study, we investigated the albumin-binding of these polyphenols by fluorescence spectroscopy, and their ability to displace the Sudlow's Site I ligand warfarin and the Site II ligand naproxen by ultrafiltration. Furthermore, the effects of CAS, IPR, and RES on CYP2C9 and CYP3A4 enzymes were examined, employing diclofenac and testosterone as substrates, respectively. Our main observations are the following: (1) Polyphenols formed stable complexes with albumin (K = 104-105 L/mol); (2) CAS and RES slightly displaced naproxen from human albumin, while albumin-binding of warfarin was not affected; (3) CAS and RES significantly inhibited CYP2C9, with CAS being as potent as the positive control warfarin; (4) each polyphenol significantly inhibited CYP3A4, with RES being stronger and CAS slightly weaker than the known inhibitor naringenin. Our results suggest that high intake of CAS and RES may interfere with the albumin-binding of Site II ligands as well as the metabolism of drugs by CYP2C9 and/or CYP3A4 enzymes, while large doses of IPR may affect the CYP3A4-catalyzed biotransformation of some drugs.


Assuntos
Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Flavonoides/farmacologia , Isoflavonas/farmacologia , Resveratrol/farmacologia , Albumina Sérica/metabolismo , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Flavonoides/química , Fluorescência , Humanos , Isoflavonas/química , Naproxeno/metabolismo , Resveratrol/química , Fatores de Tempo , Varfarina/metabolismo
18.
Biomed Pharmacother ; 102: 912-921, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29710546

RESUMO

Diosmin and silibinin (SIL) are polyphenolic compounds which are the active components of several drugs and dietary supplements. After the oral administration of diosmin (flavonoid glycoside), only its aglycone diosmetin (DIO) reaches the systemic circulation. Both DIO and SIL form complexes with serum albumin and are able to inhibit several cytochrome P450 enzymes. Therefore, it is reasonable to hypothesize that these polyphenols may displace some drugs from serum albumin and inhibit their biotransformation, potentially leading to the disruption of drug therapy. In this study, the inhibitory action of DIO and SIL on CYP2C9-catalyzed metabolism of diclofenac to 4'-hydroxydiclofenac was examined, using warfarin as a positive control. Furthermore, interaction of DIO and SIL with human and bovine serum albumins as well as the displacement of warfarin from albumin by DIO and SIL were tested, employing steady-state fluorescence spectroscopy, fluorescence anisotropy, ultrafiltration, and molecular modeling. It is demonstrated that DIO and SIL are potent inhibitors of CYP2C9 enzyme and are able to displace the Site I ligand warfarin from human serum albumin. Because DIO and SIL may interfere with the pharmacokinetics of several drugs through both ways, we need to consider the potentially hazardous consequences of the consumption of diosmin or SIL together with other drugs.


Assuntos
Inibidores do Citocromo P-450 CYP2C9/farmacologia , Flavonoides/farmacocinética , Albumina Sérica/metabolismo , Silimarina/farmacocinética , Anisotropia , Biotransformação/efeitos dos fármacos , Citocromo P-450 CYP2C9 , Diclofenaco/farmacologia , Interações Medicamentosas , Flavonoides/química , Humanos , Cinética , Simulação de Acoplamento Molecular , Soroalbumina Bovina/metabolismo , Silibina , Silimarina/química , Espectrometria de Fluorescência , Fatores de Tempo , Ultrafiltração , Varfarina
19.
Toxicol In Vitro ; 50: 249-256, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29621561

RESUMO

CYP2C9 plays a major role in drug metabolism. It is highly polymorphic and among the variants, CYP2C9*2 and CYP2C9*3 have been known to encode the protein with moderately to markedly reduced catalytic activity. Azole antifungals are among the most frequently used drugs in human pharmacotherapy and represent a widely used class of pesticides to which humans are inevitably exposed. Due to the similarities in CYP organization throughout species, azoles can interact not only with the target fungal CYP51 substrate-binding site but can also modulate the catalytic activity of human cytochrome P450s, including CYP2C9, causing severe adverse effects. In the present study the potency of azole-containing drugs and pesticides to inhibit recombinant wild-type CYP2C9*1 and the allelic variants CYP2C9*2 and CYP2C9*3 was evaluated. Significant differences were found in their affinity to CYP2C9*1, CYP2C9*2, and CYP2C9*3 as well as in the catalytic activity of CYP2C9 allelic variants. Moreover, addition of cytochrome b5 resulted in a decrease of CYP2C9*3 activity to diclofenac in a concentration-dependent manner. Increasing the knowledge of how azoles influence polymorphic variants of CYP2C9 could help individualize drug treatment, leading to optimization of the selection of drugs and doses for individuals based on genetic information.


Assuntos
Antifúngicos/farmacologia , Azóis/farmacologia , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Citocromo P-450 CYP2C9/genética , Fungicidas Industriais/farmacologia , Citocromo P-450 CYP2C9/metabolismo , Interações Medicamentosas , Escherichia coli/genética , Humanos , Polimorfismo Genético , Proteínas Recombinantes/metabolismo
20.
Int J Biochem Cell Biol ; 99: 100-108, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29627441

RESUMO

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that responds to oxidative stress and xenobiotics. Multiple lines of evidence suggest that Nrf2 activation protects against aging, inflammation, and many diseases, including cancer. Nrf2 activators derived from natural sources have been widely studied. In this study, we investigated the effect of amentoflavone (AFN), a biflavonoid found in many plants, on Nrf2 signaling in human keratinocytes (HaCaT cells). AFN significantly increased ARE luciferase activity by Nrf2 accumulation in the nucleus. Subsequently, the levels of a Nrf2 target protein, NQO-1, were significantly increased by AFN in a dose- and time-dependent manner. To verify the mechanism of AFN-induced activation of Nrf2 signaling, we measured generation of reactive oxygen species (ROS). Interestingly AFN triggered mild ROS production. Additionally, AFN-induced Nrf2 activation was inhibited by N-acetyl cysteine. Therefore, we studied the effect of ROS-related signaling on Nrf2 by measuring the activation of AKT and members of the mitogen-activated protein kinase family, such as extracellular signal-regulated kinase (ERK1/2) and p38. The results showed that the pharmacological inhibitor of PI3K/AKT (LY294002) or p38 (SB 203580), but not ERK1/2 (U0126), abrogated AFN-induced Nrf2 activation. Subsequently, we found that silencing or inhibition of p38 resulted in decrease of AKT phosphorylation as well as inhibition of Nrf2 accumulation. Furthermore, we found that AFN stabilized Nrf2 by inhibiting its ubiquitination. Taken together, our results suggest that AFN contributes to Nrf2 activation through ROS-mediated activation of the p38-AKT pathway in HaCaT cells.


Assuntos
Biflavonoides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Queratinócitos/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Células Cultivadas , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Espécies Reativas de Oxigênio , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/genética
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