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  1 / 9 MEDLINE  
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[PMID]:27600044
[Au] Autor:Desta Z; Metzger IF; Thong N; Lu JB; Callaghan JT; Skaar TC; Flockhart DA; Galinsky RE
[Ad] Endereço:Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA zdesta@iu.edu.
[Ti] Título:Inhibition of Cytochrome P450 2B6 Activity by Voriconazole Profiled Using Efavirenz Disposition in Healthy Volunteers.
[So] Source:Antimicrob Agents Chemother;60(11):6813-6822, 2016 Nov.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cytochrome P450 2B6 (CYP2B6) metabolizes clinically important drugs and other compounds. Its expression and activity vary widely among individuals, but quantitative estimation is hampered by the lack of safe and selective in vivo probes of CYP2B6 activity. Efavirenz, a nonnucleoside HIV-1 reverse transcriptase inhibitor, is mainly cleared by CYP2B6, an enzyme strongly inhibited in vitro by voriconazole. To test efavirenz metabolism as an in vivo probe of CYP2B6 activity, we quantified the inhibition of CYP2B6 activity by voriconazole in 61 healthy volunteers administered a single 100-mg oral dose of efavirenz with and without voriconazole administration. The kinetics of efavirenz metabolites demonstrated formation rate-limited elimination. Compared to control, voriconazole prolonged the elimination half-life (t ) and increased both the maximum concentration of drug in serum (C ) and the area under the concentration-time curve from 0 h to t (AUC ) of efavirenz (mean change of 51%, 36%, and 89%, respectively) (P < 0.0001) with marked intersubject variability (e.g., the percent change in efavirenz AUC ranged from 0.4% to ∼224%). Voriconazole decreased efavirenz 8-hydroxylation by greater than 60% (P < 0.0001), whereas its effect on 7-hydroxylation was marginal. The plasma concentration ratio of efavirenz to 8-hydroxyefavirenz, determined 1 to 6 h after dosing, was significantly increased by voriconazole and correlated with the efavirenz AUC (Pearson r = >0.8; P < 0.0001). This study demonstrates the mechanisms of voriconazole-efavirenz interaction, establishes the use of a low dose of efavirenz as a safe and selective in vivo probe for phenotyping CYP2B6 activity, and identifies several easy-to-use indices that should enhance understanding of the mechanisms of CYP2B6 interindividual variability. (This study is registered at ClinicalTrials.gov under identifier NCT01104376.).
[Mh] Termos MeSH primário: Benzoxazinas/farmacocinética
Inibidores do Citocromo P-450 CYP2B6/farmacologia
Citocromo P-450 CYP2B6/sangue
Voriconazol/farmacologia
[Mh] Termos MeSH secundário: Administração Oral
Adolescente
Adulto
Inibidores do Citocromo P-450 CYP2B6/administração & dosagem
Inibidores do Citocromo P-450 CYP2B6/farmacocinética
Feminino
Voluntários Saudáveis
Seres Humanos
Inativação Metabólica
Masculino
Meia-Idade
Voriconazol/administração & dosagem
Voriconazol/farmacocinética
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzoxazines); 0 (Cytochrome P-450 CYP2B6 Inhibitors); EC 1.14.14.1 (CYP2B6 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2B6); JE6H2O27P8 (efavirenz); JFU09I87TR (Voriconazole)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170915
[Lr] Data última revisão:
170915
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160908
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1128/AAC.01000-16


  2 / 9 MEDLINE  
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[PMID]:27387538
[Au] Autor:Bhateria M; Ramakrishna R; Puttrevu SK; Saxena AK; Bhatta RS
[Ad] Endereço:Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226032, Uttar Pradesh, India; Academy of Scientific and Innovative Research, New Delhi 110001, India.
[Ti] Título:Enantioselective inhibition of Cytochrome P450-mediated drug metabolism by a novel antithrombotic agent, S002-333: Major effect on CYP2B6.
[So] Source:Chem Biol Interact;256:257-65, 2016 Aug 25.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:A significant number of new chemical entities (NCEs) fail in drug discovery due to inhibition of Cytochrome P450 (CYP) enzymes. Therefore, to avert costly drug failure at the clinical phase it becomes indispensable to evaluate the CYP inhibition profile of NCEs early in drug discovery. In light of these concerns, we envisioned to investigate the inhibitory effects of S002-333 [2-(4-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-b-carboxylic acid amide], a novel and potent antithrombotic agent, on nine major CYP enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4) of human liver microsomes (HLM). S002-333 exists as racemic mixture of S004-1032 (R-isomer) and S007-1558 (S-isomer), consequently, we further examined the enantioselective differences of S002-333 in the inhibition of human CYP enzymes. Of the CYP enzymes tested, CYP2B6-catalyzed bupropion 6-hydroxylation was inhibited by S002-333 (IC50 âˆ¼ 9.25 ± 2.46 µM) in a stereoselective manner with (S)-isomer showing potent inhibition (IC50 âˆ¼ 5.28 ± 1.25 µM) in contrast to (R)-isomer which showed negligible inhibition on CYP2B6 activity (IC50 > 50 µM). S002-333 and its (S)-isomer inhibited CYP2B6 activity in a non-competitive fashion with estimated Ki values of 10.1 ± 3.4 µM and 5.09 ± 1.05 µM, respectively. No shift in the IC50 value was observed for S002-333 and its isomers when preincubated for 30 min in the presence of NADPH suggesting that neither S002-333 nor its enantiomers are time-dependent inhibitors. Thus, the present findings signified that S002-333 is a potent stereoselective inhibitor of CYP2B6, whereas, inhibition for other CYPs was substantially negligible. These in vitro findings would be useful in deciding the development of S002-333 as a single-enantiomer or as a racemic mixture.
[Mh] Termos MeSH primário: Carbolinas/metabolismo
Inibidores do Citocromo P-450 CYP2B6/metabolismo
Citocromo P-450 CYP2B6/metabolismo
Fibrinolíticos/metabolismo
Sulfonamidas/metabolismo
[Mh] Termos MeSH secundário: Carbolinas/química
Inibidores do Citocromo P-450 CYP2B6/química
Inibidores das Enzimas do Citocromo P-450/química
Inibidores das Enzimas do Citocromo P-450/metabolismo
Sistema Enzimático do Citocromo P-450/metabolismo
Fibrinolíticos/química
Seres Humanos
Microssomos Hepáticos/efeitos dos fármacos
Microssomos Hepáticos/metabolismo
Isoformas de Proteínas/metabolismo
Estereoisomerismo
Sulfonamidas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-(4'-methoxybenzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole-3-carboxylic acid amide); 0 (Carbolines); 0 (Cytochrome P-450 CYP2B6 Inhibitors); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Fibrinolytic Agents); 0 (Protein Isoforms); 0 (Sulfonamides); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.14.1 (Cytochrome P-450 CYP2B6)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170130
[Lr] Data última revisão:
170130
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160709
[St] Status:MEDLINE


  3 / 9 MEDLINE  
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[PMID]:27311985
[Au] Autor:Jin Y; Yu D; Tolleson WH; Knox B; Wang Y; Chen S; Ren Z; Deng H; Guo Y; Ning B
[Ad] Endereço:Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China.
[Ti] Título:MicroRNA hsa-miR-25-3p suppresses the expression and drug induction of CYP2B6 in human hepatocytes.
[So] Source:Biochem Pharmacol;113:88-96, 2016 Aug 01.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cytochrome P450 2B6 (CYP2B6), mainly expressed in the liver and brain, is important for processing a number of widely used drugs. Variations in CYP2B6 expression are associated with decreased drug efficacy or adverse effects in some patients. Although CYP2B6 genetic variants are associated with its differential expression, epigenetic mechanisms affecting CYP2B6 gene regulation have not been established. Sequence analysis identified 29 domains in the CYP2B6 mRNA transcript that could be subject to regulation by microRNAs. Inverse correlations were found in human hepatocytes for the levels of the microRNAs hsa-miR-504-5p and hsa-miR-25-3p compared with CYP2B6 mRNA. Reporter gene assays showed that hsa-miR-25-3p suppresses CYP2B6 expression by targeting a specific sequence in the 3'-untranslated region of the mRNA transcript. Electrophoretic mobility shift assays confirmed that hsa-miR-25-3p forms stable complexes with its cognate mRNA sequence and that it recruits cellular factors, including Ago-4. Transfection of HepaRG cells with hsa-miR-25-3p mimics inhibited expression of the endogenous CYP2B6 gene and it also decreased rifampicin-dependent induction of CYP2B6 at the mRNA and protein levels. In summary, in silico and in vitro analyses show that hsa-miR-25-3p suppresses CYP2B6 expression in human liver cells via an epigenetic mechanism.
[Mh] Termos MeSH primário: Citocromo P-450 CYP2B6/genética
Citocromo P-450 CYP2B6/metabolismo
Epigênese Genética
Regulação Enzimológica da Expressão Gênica
Hepatócitos/metabolismo
MicroRNAs/genética
[Mh] Termos MeSH secundário: Sítios de Ligação
Técnicas de Cultura de Células
Linhagem Celular Tumoral
Inibidores do Citocromo P-450 CYP2B6/farmacologia
Ensaio de Desvio de Mobilidade Eletroforética
Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos
Hepatócitos/efeitos dos fármacos
Seres Humanos
Fígado/metabolismo
MicroRNAs/metabolismo
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Rifampina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2B6 Inhibitors); 0 (MIRN25 microRNA, human); 0 (MicroRNAs); 0 (RNA, Messenger); EC 1.14.14.1 (CYP2B6 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2B6); VJT6J7R4TR (Rifampin)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160618
[St] Status:MEDLINE


  4 / 9 MEDLINE  
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[PMID]:26891286
[Au] Autor:Thomford NE; Awortwe C; Dzobo K; Adu F; Chopera D; Wonkam A; Skelton M; Blackhurst D; Dandara C
[Ad] Endereço:Division of Human Genetics, Department of Pathology & Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa. THMNIC023@myuct.ac.za.
[Ti] Título:Inhibition of CYP2B6 by Medicinal Plant Extracts: Implication for Use of Efavirenz and Nevirapine-Based Highly Active Anti-Retroviral Therapy (HAART) in Resource-Limited Settings.
[So] Source:Molecules;21(2), 2016 Feb 16.
[Is] ISSN:1420-3049
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Highly active antiretroviral therapy (HAART) has greatly improved health parameters of HIV infected individuals. However, there are several challenges associated with the chronic nature of HAART administration. For populations in health transition, dual use of medicinal plant extracts and conventional medicine poses a significant challenge. There is need to evaluate interactions between commonly used medicinal plant extracts and antiretroviral drugs used against HIV/AIDS. Efavirenz (EFV) and nevirapine (NVP) are the major components of HAART both metabolized by CYP2B6, an enzyme that can potentially be inhibited or induced by compounds found in medicinal plant extracts. The purpose of this study was to evaluate the effects of extracts of selected commonly used medicinal plants on CYP2B6 enzyme activity. Recombinant human CYP2B6 was used to evaluate inhibition, allowing the assessment of herb-drug interactions (HDI) of medicinal plants Hyptis suaveolens, Myrothamnus flabellifolius, Launaea taraxacifolia, Boerhavia diffusa and Newbouldia laevis. The potential of these medicinal extracts to cause HDI was ranked accordingly for reversible inhibition and also classified as potential time-dependent inhibitor (TDI) candidates. The most potent inhibitor for CYP2B6 was Hyptis suaveolens extract (IC50 = 19.09 ± 1.16 µg/mL), followed by Myrothamnus flabellifolius extract (IC50 = 23.66 ± 4.86 µg/mL), Launaea taraxacifolia extract (IC50 = 33.87 ± 1.54 µg/mL), and Boerhavia diffusa extract (IC50 = 34.93 ± 1.06 µg/mL). Newbouldia laevis extract, however, exhibited weak inhibitory effects (IC50 = 100 ± 8.71 µg/mL) on CYP2B6. Launaea taraxacifolia exhibited a TDI (3.17) effect on CYP2B6 and showed a high concentration of known CYP450 inhibitory phenolic compounds, chlorogenic acid and caffeic acid. The implication for these observations is that drugs that are metabolized by CYP2B6 when co-administered with these herbal medicines and when adequate amounts of the extracts reach the liver, there is a high likelihood of standard doses affecting drug plasma concentrations which could lead to toxicity.
[Mh] Termos MeSH primário: Extratos Vegetais/química
Extratos Vegetais/farmacologia
Plantas Medicinais/química
[Mh] Termos MeSH secundário: Terapia Antirretroviral de Alta Atividade
Benzoxazinas/farmacologia
Citocromo P-450 CYP2B6/genética
Citocromo P-450 CYP2B6/metabolismo
Inibidores do Citocromo P-450 CYP2B6/química
Inibidores do Citocromo P-450 CYP2B6/farmacologia
Interações Ervas-Drogas
Seres Humanos
Magnoliopsida/química
Nevirapina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Benzoxazines); 0 (Cytochrome P-450 CYP2B6 Inhibitors); 0 (Plant Extracts); 99DK7FVK1H (Nevirapine); EC 1.14.14.1 (CYP2B6 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2B6); JE6H2O27P8 (efavirenz)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160219
[St] Status:MEDLINE


  5 / 9 MEDLINE  
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[PMID]:26648056
[Au] Autor:Raunio H; Juvonen RO; Poso A; Lahtela-Kakkonen M; Rahnasto-Rilla M
[Ad] Endereço:School of Pharmacy, University of Eastern Finland, Box 1627, 70211 Kuopio, Finland.. hannu.raunio@uef.fi.
[Ti] Título:Common and Distinct Interactions of Chemical Inhibitors with Cytochrome P450 CYP1A2, CYP2A6 and CYP2B6 Enzymes.
[So] Source:Drug Metab Lett;10(1):56-64, 2016.
[Is] ISSN:1874-0758
[Cp] País de publicação:United Arab Emirates
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Tobacco smoking is a leading cause of preventable disease and death globally. Nicotine is the main addictive component in tobacco. Nicotine is eliminated from the body by biotransformation in the liver to inactive metabolites. This reaction is catalyzed by the cytochrome P450 2A6 (CYP2A6) enzyme. Administering chemical inhibitors of CYP2A6 has been shown to slow down the elimination of nicotine with consequent reduction in number of cigarettes smoked. We have systematically developed small molecule CYP2A6 inhibitors with good balance between potency and CYP selectivity. OBJECTIVE: During this process we have noticed that many potent CYP2A6 inhibitors also inhibit other human liver CYP forms, most notably CYP1A2 and CYP2B6. This study aimed at defining common and distinct features of ligand binding to CYP1A2, CYP2A6 and CYP2B6 active sites. METHODS: We used our previous chemical inhibitor databases to construct improved 3-dimensional quantitative structureactivity relationship (3D-QSAR) models for CYP1A2, CYP2A6 and CYP2B6. RESULTS: Combined 3D-QSAR and docking procedures yielded precise information about the common and distinct interactions of inhibitors and the enzyme active sites. Positioning of hydrogen bond donor/acceptor atoms and the shape and volume of the compound defined the potency and specificity of inhibition. A novel potent and selective CYP1A2 inhibitor was found. CONCLUSION: This in silico approach will provide a means for very rapid and high throughput prediction of cross-inhibition of these three CYP enzymes.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP1A2/farmacologia
Citocromo P-450 CYP1A2/metabolismo
Citocromo P-450 CYP2A6/metabolismo
Inibidores do Citocromo P-450 CYP2B6/farmacologia
Citocromo P-450 CYP2B6/metabolismo
Desenho de Drogas
[Mh] Termos MeSH secundário: Domínio Catalítico
Projeto Auxiliado por Computador
Citocromo P-450 CYP1A2/química
Inibidores do Citocromo P-450 CYP1A2/química
Inibidores do Citocromo P-450 CYP1A2/metabolismo
Citocromo P-450 CYP2A6/química
Citocromo P-450 CYP2B6/química
Inibidores do Citocromo P-450 CYP2B6/química
Inibidores do Citocromo P-450 CYP2B6/metabolismo
Seres Humanos
Ligações de Hidrogênio
Ligantes
Simulação de Acoplamento Molecular
Estrutura Molecular
Ligação Proteica
Conformação Proteica
Relação Quantitativa Estrutura-Atividade
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP1A2 Inhibitors); 0 (Cytochrome P-450 CYP2B6 Inhibitors); 0 (Ligands); EC 1.14.14.1 (CYP1A2 protein, human); EC 1.14.14.1 (CYP2A6 protein, human); EC 1.14.14.1 (CYP2B6 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP1A2); EC 1.14.14.1 (Cytochrome P-450 CYP2A6); EC 1.14.14.1 (Cytochrome P-450 CYP2B6)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151210
[St] Status:MEDLINE


  6 / 9 MEDLINE  
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[PMID]:26335194
[Au] Autor:Ji L; Lu D; Cao J; Zheng L; Peng Y; Zheng J
[Ad] Endereço:College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
[Ti] Título:Psoralen, a mechanism-based inactivator of CYP2B6.
[So] Source:Chem Biol Interact;240:346-52, 2015 Oct 05.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Furanocoumarin compound psoralen (PRN) is a major active ingredient found in herbaceous plants. PRN has been used for the treatment of various dermal diseases in China. We evaluated the inhibitory effect of PRN on cytochrome P450 2B6 (CYP2B6) and found that PRN induced a time-, concentration-, and NADPH-dependent inactivation of CYP2B6 with the values of KI and kinact being 110.2 µM and 0.200 min(-1), respectively. Ticlopidine, a CYP2B6 substrate, prevented the enzyme from the inactivation induced by PRN. Exogenous nucleophile glutathione (GSH) and catalase/superoxide dismutase showed limited protection of CYP2B6 from the inactivation. The estimated partition ratio of the inactivation was approximately 400. GSH trapping experiments indicates that an epoxide or/and γ-ketoenal intermediate was formed in microsomal incubations with PRN. In summary, PRN was characterized as a mechanism-based inactivator of CYP2B6.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP2B6/farmacologia
Citocromo P-450 CYP2B6/metabolismo
Ficusina/farmacologia
[Mh] Termos MeSH secundário: Citocromo P-450 CYP2B6/química
Inibidores do Citocromo P-450 CYP2B6/química
Relação Dose-Resposta a Droga
Ativação Enzimática/efeitos dos fármacos
Ficusina/química
Ticlopidina/metabolismo
Ticlopidina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2B6 Inhibitors); EC 1.14.14.1 (Cytochrome P-450 CYP2B6); KTZ7ZCN2EX (Ficusin); OM90ZUW7M1 (Ticlopidine)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:151121
[Lr] Data última revisão:
151121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150904
[St] Status:MEDLINE


  7 / 9 MEDLINE  
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[PMID]:26191268
[Au] Autor:Lin K; Zhang Q; Liu Z; Yang S; Lin Y; Wen C; Zheng Y
[Ad] Endereço:Medical Experimental Teaching Center, Wenzhou Medical University Wenzhou 325035, China.
[Ti] Título:Effects of suberoylanilide hydroxamic acid on rat cytochrome P450 enzyme activities.
[So] Source:Int J Clin Exp Pathol;8(5):5584-90, 2015.
[Is] ISSN:1936-2625
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Vorinostat (suberoylanilide hydroxamic acid, SAHA) is the first approved histone deacetylase (HDAC) inhibitor for the treatment of cutaneous T-cell lymphoma after progressive disease following two systemic therapies. The rats were randomly divided into SAHA groups (low, medium and high dosage) and control group. The SAHA group rats were given 12.3, 24.5, and 49 mg/kg SAHA, respectively, by continuous intragastric administration for 7 days. The influence of SAHA on the activities of CYP450 isoforms CYP2B6, CYP1A2, CYP2C19, CYP2D6 and CYP2C9 were evaluated by cocktail method, they were responsed by the changes of pharmacokinetic parameters of bupropion, phenacetin, tolbutamide, metroprolol and omeprazole. The five probe drugs were given to rats through intragastric administration, and the plasma concentration were determined by UPLC-MS/MS. The result of SAHA group compared to control group, there were statistical pharmacokinetics difference for bupropion, phenacetin, tolbutamide and metroprolol. Continuous intragastric administration for 7 days may induce the activities of CYP2C19 of rats, inhibit CYP1A2 and slightly inhibit CYP2B6 and CYP2D6 of rats. This may give advising for reasonable drug use after co-used with SAHA. The results indicated that drug co-administrated with SAHA may need dose adjustment. Furthermore, continuous intragastric administration of SAHA for 7 days, liver cell damaged, causing liver cell edema, in liver metabolism process.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP1A2/administração & dosagem
Indutores do Citocromo P-450 CYP2C19/administração & dosagem
Citocromo P-450 CYP2C19/biossíntese
Citocromos/antagonistas & inibidores
Inibidores de Histona Desacetilases/administração & dosagem
Ácidos Hidroxâmicos/administração & dosagem
Fígado/efeitos dos fármacos
[Mh] Termos MeSH secundário: Administração Oral
Animais
Bupropiona/sangue
Bupropiona/farmacocinética
Doença Hepática Induzida por Substâncias e Drogas/etiologia
Doença Hepática Induzida por Substâncias e Drogas/patologia
Cromatografia Líquida
Citocromo P-450 CYP1A2
Inibidores do Citocromo P-450 CYP1A2/toxicidade
Citocromo P-450 CYP2B6/metabolismo
Inibidores do Citocromo P-450 CYP2B6/administração & dosagem
Indutores do Citocromo P-450 CYP2C19/toxicidade
Citocromo P-450 CYP2D6/metabolismo
Inibidores do Citocromo P-450 CYP2D6/administração & dosagem
Citocromos/metabolismo
Interações Medicamentosas
Edema/induzido quimicamente
Edema/patologia
Indução Enzimática
Inibidores de Histona Desacetilases/toxicidade
Ácidos Hidroxâmicos/toxicidade
Fígado/enzimologia
Fígado/patologia
Masculino
Metoprolol/sangue
Metoprolol/farmacocinética
Omeprazol/sangue
Omeprazol/farmacocinética
Fenacetina/sangue
Fenacetina/farmacocinética
Ratos Sprague-Dawley
Especificidade por Substrato
Espectrometria de Massas em Tandem
Tolbutamida/sangue
Tolbutamida/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP1A2 Inhibitors); 0 (Cytochrome P-450 CYP2B6 Inhibitors); 0 (Cytochrome P-450 CYP2C19 Inducers); 0 (Cytochrome P-450 CYP2D6 Inhibitors); 0 (Cytochromes); 0 (Histone Deacetylase Inhibitors); 0 (Hydroxamic Acids); 01ZG3TPX31 (Bupropion); 58IFB293JI (vorinostat); 982XCM1FOI (Tolbutamide); EC 1.14.14.1 (Cyp1a2 protein, rat); EC 1.14.14.1 (Cytochrome P-450 CYP1A2); EC 1.14.14.1 (Cytochrome P-450 CYP2B6); EC 1.14.14.1 (Cytochrome P-450 CYP2C19); EC 1.14.14.1 (Cytochrome P-450 CYP2D6); ER0CTH01H9 (Phenacetin); GEB06NHM23 (Metoprolol); KG60484QX9 (Omeprazole)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150721
[St] Status:MEDLINE


  8 / 9 MEDLINE  
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[PMID]:25656918
[Au] Autor:Nirogi R; Palacharla RC; Mohammed AR; Manoharan A; Ponnamaneni RK; Bhyrapuneni G
[Ad] Endereço:Discovery Research, Suven Life Sciences Limited, Serene Chambers, Road -5, Avenue -7, Banjara Hills, Hyderabad 500034, India. Electronic address: nvsrk@suven.com.
[Ti] Título:Evaluation of metabolism dependent inhibition of CYP2B6 mediated bupropion hydroxylation in human liver microsomes by monoamine oxidase inhibitors and prediction of potential as perpetrators of drug interaction.
[So] Source:Chem Biol Interact;230:9-20, 2015 Mar 25.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:The objective of the study was to evaluate the metabolism dependent inhibition of CYP2B6 catalyzed bupropion hydroxylation in human liver microsomes by monoamine oxidase (MAO) inhibitors and to predict the drug-drug interaction potential of monoamine oxidase inhibitors as perpetrators of drug interaction. Human liver microsomal CYP2B6 activities were investigated using bupropion hydroxylation as probe substrate marker. The results from single point time dependent inhibition and shift assays suggest that clorgyline, pargyline, phenelzine, and selegiline were metabolism based inhibitors of CYP2B6. In IC50 shift assays, clorgyline, pargyline, phenelzine and selegiline are metabolism based inhibitors of CYP2B6 with fold shit of 3.0-, 3.7-, 2.9-, and 11.4-fold respectively. The inactivation of clorgyline was characterized by KI value of 2.5 ± 0.3 and k(inact) value of 0.045 ± 0.001 min(-1). Phenelzine inactivated CYP2B6 with KI and k(inact) values of 44.9 ± 6.9 µM and 0.085 ± 0.003 min(-1) respectively. Inactivation of selegiline was characterized with KI and k(inact) values of 22.0 ± 3.3 and 0.074 ± 0.002 min(-1) respectively. The inactivation caused by these inhibitors was not reversed by dialysis indicating irreversible inhibition. Based on the mechanistic static model, selegiline showed an increase in the area under the curve (AUC) of efavirenz and bupropion by 1.01-fold. Phenelzine predicted to cause an increase in the AUC of efavirenz and bupropion by 9.4- and 2.4-fold respectively considering unbound hepatic inlet concentrations of phenelzine. In conclusion, the results from this study demonstrated that MAO inhibitors can inactivate human liver microsomal CYP2B6. The likelihood of drug interaction when selegiline co-administered with CYP2B6 substrates is remote. Caution is required while co-administering phenelzine with substrates that are exclusively metabolized by CYP2B6 enzyme and substrates that have narrow therapeutic index.
[Mh] Termos MeSH primário: Bupropiona/farmacocinética
Inibidores do Citocromo P-450 CYP2B6/farmacologia
Citocromo P-450 CYP2B6/metabolismo
Microssomos Hepáticos/efeitos dos fármacos
Inibidores da Monoaminoxidase/farmacologia
[Mh] Termos MeSH secundário: Bupropiona/metabolismo
Clorgilina/farmacologia
Interações Medicamentosas
Glutationa/metabolismo
Seres Humanos
Hidroxilação
Concentração Inibidora 50
Cinésica
Microssomos Hepáticos/metabolismo
Inibidores da Monoaminoxidase/química
Pargilina/farmacologia
Fenelzina/farmacologia
Selegilina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2B6 Inhibitors); 0 (Monoamine Oxidase Inhibitors); 01ZG3TPX31 (Bupropion); 2K1V7GP655 (Selegiline); 9MV14S8G3E (Pargyline); EC 1.14.14.1 (CYP2B6 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2B6); GAN16C9B8O (Glutathione); LYJ16FZU9Q (Clorgyline); O408N561GF (Phenelzine)
[Em] Mês de entrada:1506
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150207
[St] Status:MEDLINE


  9 / 9 MEDLINE  
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[PMID]:25409894
[Au] Autor:Liu Z; Li L; Wu H; Hu J; Ma J; Zhang QY; Ding X
[Ad] Endereço:Wadsworth Center, New York State Department of Health, and School of Public Health, University at Albany, Albany, New York (Z.L., L.L., H.W., J.H., J.M., Q.-Y.Z., X.D.); and College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York (X.D.).
[Ti] Título:Characterization of CYP2B6 in a CYP2B6-humanized mouse model: inducibility in the liver by phenobarbital and dexamethasone and role in nicotine metabolism in vivo.
[So] Source:Drug Metab Dispos;43(2):208-16, 2015 Feb.
[Is] ISSN:1521-009X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The aim of this study was to further characterize the expression and function of human CYP2B6 in a recently generated CYP2A13/2B6/2F1-transgenic (TG) mouse model, in which CYP2B6 is expressed selectively in the liver. The inducibility of CYP2B6 by phenobarbital (PB) and dexamethasone (DEX), known inducers of CYP2B6 in human liver, was examined in the TG mice, as well as in TG/Cyp2abfgs-null (or "CYP2B6-humanized") mice. Hepatic expression of CYP2B6 mRNA and protein was greatly induced by PB or DEX treatment in both TG and TG/Cyp2abfgs-null mice. Function of the transgenic CYP2B6 was first studied using bupropion as a probe substrate. In PB-treated mice, the rates of hepatic microsomal hydroxybupropion formation (at 50 µM bupropion) were >4-fold higher in TG/Cyp2abfgs-null than in Cyp2abfgs-null mice (for both male and female mice); the rate difference was accompanied by a 5-fold higher catalytic efficiency in the TG/Cyp2abfgs-null mice and was abolished by an antibody to CYP2B6. The ability of CYP2B6 to metabolize nicotine was then examined, both in vitro and in vivo. The rates of hepatic microsomal cotinine formation from nicotine were significantly higher in TG/Cyp2abfgs-null than in Cyp2abfgs-null mice, pretreated with PB or DEX. Furthermore, systemic nicotine metabolism was faster in TG/Cyp2abfgs-null than in Cyp2abfgs-null mice. Thus, the transgenic CYP2B6 was inducible and functional, and, in the absence of mouse CYP2A and CYP2B enzymes, it contributed to nicotine metabolism in vivo. The CYP2B6-humanized mouse will be valuable for studies on in vivo roles of hepatic CYP2B6 in xenobiotic metabolism and toxicity.
[Mh] Termos MeSH primário: Indutores do Citocromo P-450 CYP2B6/farmacologia
Citocromo P-450 CYP2B6/metabolismo
Dexametasona/farmacologia
Fígado/efeitos dos fármacos
Nicotina/metabolismo
Fenobarbital/farmacologia
[Mh] Termos MeSH secundário: Animais
Anti-Inflamatórios/farmacologia
Hidrocarboneto de Aril Hidroxilases/genética
Hidrocarboneto de Aril Hidroxilases/metabolismo
Citocromo P-450 CYP2B6/química
Citocromo P-450 CYP2B6/genética
Inibidores do Citocromo P-450 CYP2B6/farmacologia
Sistema Enzimático do Citocromo P-450/genética
Sistema Enzimático do Citocromo P-450/metabolismo
Indução Enzimática/efeitos dos fármacos
Feminino
Seres Humanos
Hipnóticos e Sedativos/farmacologia
Fígado/enzimologia
Fígado/metabolismo
Masculino
Camundongos Endogâmicos C57BL
Camundongos Knockout
Camundongos Transgênicos
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents); 0 (Cytochrome P-450 CYP2B6 Inducers); 0 (Cytochrome P-450 CYP2B6 Inhibitors); 0 (Hypnotics and Sedatives); 0 (Recombinant Proteins); 6M3C89ZY6R (Nicotine); 7S5I7G3JQL (Dexamethasone); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases); EC 1.14.14.1 (CYP2B6 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2B6); YQE403BP4D (Phenobarbital)
[Em] Mês de entrada:1511
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141121
[St] Status:MEDLINE
[do] DOI:10.1124/dmd.114.061812



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