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[PMID]:28461575
[Au] Autor:Phuc NM; Wu Z; O Y; Lee JH; Oh S; Song GY; Liu KH
[Ad] Endereço:BK21 Plus KNU Multi-Omics-Based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea (N.M.P., Z.W., K.-H.L.); College of Pharmacy, Chungnam National University, Daejeon, Korea (Y.O., J.-H.L., G.-Y.S.); and Dep
[Ti] Título:LKY-047: First Selective Inhibitor of Cytochrome P450 2J2.
[So] Source:Drug Metab Dispos;45(7):765-769, 2017 Jul.
[Is] ISSN:1521-009X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Highly selective cytochrome P450 CYP2J2 (CYP2J2) inhibitors suitable for reaction phenotyping are currently not available. (7 )-(+)-(4-Nitro-phenyl)-acrylic acid, 8,8-dimethyl-2-oxo-6,7-dihydro- -pyrano[3,2-g]chromen-7-yl-ester (LKY-047), a decursin derivative, was synthesized, and its inhibitor potencies toward CYP2J2 as well as other cytochrome P450 (P450) enzymes in human liver microsomes (HLM) were evaluated. LKY-047 was demonstrated to be a strong competitive inhibitor of CYP2J2-mediated astemizole -demethylase and terfenadine hydroxylase activity, with values of 0.96 and 2.61 M, respectively. It also acted as an uncompetitive inhibitor of CYP2J2-mediated ebastine hydroxylation with a value of 3.61 M. Preincubation of LKY-047 with HLMs and NADPH did not alter inhibition potency, indicating that it is not a mechanism-based inhibitor. LKY-047 was found to be a selective CYP2J2 inhibitor with no inhibitory effect on other human P450s, such as CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A (IC > 50 M). These in vitro data support the use of LKY-047 as a selective CYP2J2 inhibitor with potential application in the identification of P450 isoforms responsible for drug metabolism in reaction phenotyping assays.
[Mh] Termos MeSH primário: Inibidores das Enzimas do Citocromo P-450/farmacologia
Sistema Enzimático do Citocromo P-450/metabolismo
[Mh] Termos MeSH secundário: Seres Humanos
Hidroxilação/efeitos dos fármacos
Inativação Metabólica/efeitos dos fármacos
Microssomos Hepáticos/efeitos dos fármacos
Microssomos Hepáticos/metabolismo
NADP/metabolismo
Isoformas de Proteínas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Protein Isoforms); 53-59-8 (NADP); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.14.1 (arachidonate epoxygenase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1124/dmd.117.075036


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[PMID]:29329342
[Au] Autor:Ahmad M; Suhaimi SN; Chu TL; Abdul Aziz N; Mohd Kornain NK; Samiulla DS; Lo KW; Ng CH; Khoo AS
[Ad] Endereço:Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur, Malaysia.
[Ti] Título:Ternary copper(II) complex: NCI60 screening, toxicity studies, and evaluation of efficacy in xenograft models of nasopharyngeal carcinoma.
[So] Source:PLoS One;13(1):e0191295, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Copper(II) ternary complex, [Cu(phen)(C-dmg)(H2O)]NO3 was evaluated against a panel of cell lines, tested for in vivo efficacy in nasopharyngeal carcinoma xenograft models as well as for toxicity in NOD scid gamma mice. The Cu(II) complex displayed broad spectrum cytotoxicity against multiple cancer types, including lung, colon, central nervous system, melanoma, ovarian, and prostate cancer cell lines in the NCI-60 panel. The Cu(II) complex did not cause significant induction of cytochrome P450 (CYP) 3A and 1A enzymes but moderately inhibited CYP isoforms 1A2, 2C9, 2C19, 2D6, 2B6, 2C8 and 3A4. The complex significantly inhibited tumor growth in nasopharyngeal carcinoma xenograft bearing mice models at doses which were well tolerated without causing significant or permanent toxic side effects. However, higher doses which resulted in better inhibition of tumor growth also resulted in toxicity.
[Mh] Termos MeSH primário: Antineoplásicos/química
Antineoplásicos/farmacologia
Carcinoma/tratamento farmacológico
Cobre/química
Neoplasias Nasofaríngeas/tratamento farmacológico
Compostos Organometálicos/química
Compostos Organometálicos/farmacologia
Ensaios Antitumorais Modelo de Xenoenxerto
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/toxicidade
Carcinoma/patologia
Linhagem Celular Tumoral
Inibidores das Enzimas do Citocromo P-450/química
Inibidores das Enzimas do Citocromo P-450/farmacologia
Inibidores das Enzimas do Citocromo P-450/toxicidade
Sistema Enzimático do Citocromo P-450/biossíntese
Sistema Enzimático do Citocromo P-450/metabolismo
Relação Dose-Resposta a Droga
Indução Enzimática/efeitos dos fármacos
Feminino
Hepatócitos/efeitos dos fármacos
Camundongos
Neoplasias Nasofaríngeas/patologia
Compostos Organometálicos/toxicidade
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Organometallic Compounds); 789U1901C5 (Copper); 9035-51-2 (Cytochrome P-450 Enzyme System)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180113
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191295


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[PMID]:29227934
[Au] Autor:Zabela V; Hettich T; Schlotterbeck G; Wimmer L; Mihovilovic MD; Guillet F; Bouaita B; Shevchenko B; Hamburger M; Oufir M
[Ad] Endereço:Pharmaceutical Biology Laboratory, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: volha.zabela@unibas.ch.
[Ti] Título:GABA receptor activity modulating piperine analogs: In vitro metabolic stability, metabolite identification, CYP450 reaction phenotyping, and protein binding.
[So] Source:J Chromatogr B Analyt Technol Biomed Life Sci;1072:379-389, 2018 Jan 01.
[Is] ISSN:1873-376X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:In a screening of natural products for allosteric modulators of GABA receptors (γ-aminobutyric acid type A receptor), piperine was identified as a compound targeting a benzodiazepine-independent binding site. Given that piperine is also an activator of TRPV1 (transient receptor potential vanilloid type 1) receptors involved in pain signaling and thermoregulation, a series of piperine analogs were prepared in several cycles of structural optimization, with the aim of separating GABA and TRPV1 activating properties. We here investigated the metabolism of piperine and selected analogs in view of further cycles of lead optimization. Metabolic stability of the compounds was evaluated by incubation with pooled human liver microsomes, and metabolites were analyzed by UHPLC-Q-TOF-MS. CYP450 isoenzymes involved in metabolism of compounds were identified by reaction phenotyping with Silensomes™. Unbound fraction in whole blood was determined by rapid equilibrium dialysis. Piperine was the metabolically most stable compound. Aliphatic hydroxylation, and N- and O-dealkylation were the major routes of oxidative metabolism. Piperine was exclusively metabolized by CYP1A2, whereas CYP2C9 contributed significantly in the oxidative metabolism of all analogs. Extensive binding to blood constituents was observed for all compounds.
[Mh] Termos MeSH primário: Alcaloides
Benzodioxóis
Inibidores das Enzimas do Citocromo P-450
Sistema Enzimático do Citocromo P-450
Piperidinas
Alcamidas Poli-Insaturadas
Receptores de GABA-A/metabolismo
[Mh] Termos MeSH secundário: Alcaloides/análise
Alcaloides/química
Alcaloides/metabolismo
Benzodioxóis/análise
Benzodioxóis/química
Benzodioxóis/metabolismo
Cromatografia Líquida de Alta Pressão
Inibidores das Enzimas do Citocromo P-450/análise
Inibidores das Enzimas do Citocromo P-450/química
Inibidores das Enzimas do Citocromo P-450/metabolismo
Sistema Enzimático do Citocromo P-450/análise
Sistema Enzimático do Citocromo P-450/classificação
Sistema Enzimático do Citocromo P-450/metabolismo
Seres Humanos
Microssomos Hepáticos/metabolismo
Piperidinas/análise
Piperidinas/química
Piperidinas/metabolismo
Alcamidas Poli-Insaturadas/análise
Alcamidas Poli-Insaturadas/química
Alcamidas Poli-Insaturadas/metabolismo
Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Alkaloids); 0 (Benzodioxoles); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Piperidines); 0 (Polyunsaturated Alkamides); 0 (Receptors, GABA-A); 9035-51-2 (Cytochrome P-450 Enzyme System); U71XL721QK (piperine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171212
[St] Status:MEDLINE


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[PMID]:28468305
[Au] Autor:Kim JH; Kwon SS; Jeong HU; Lee HS
[Ad] Endereço:Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Korea. jhyunkim@catholic.ac.kr.
[Ti] Título:Inhibitory Effects of Dimethyllirioresinol, Epimagnolin A, Eudesmin, Fargesin, and Magnolin on Cytochrome P450 Enzyme Activities in Human Liver Microsomes.
[So] Source:Int J Mol Sci;18(5), 2017 May 01.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Magnolin, epimagnolin A, dimethyllirioresinol, eudesmin, and fargesin are pharmacologically active tetrahydrofurofuranoid lignans found in Flos Magnoliae. The inhibitory potentials of dimethyllirioresinol, epimagnolin A, eudesmin, fargesin, and magnolin on eight major human cytochrome P450 (CYP) enzyme activities in human liver microsomes were evaluated using liquid chromatography-tandem mass spectrometry to determine the inhibition mechanisms and inhibition potency. Fargesin inhibited CYP2C9-catalyzed diclofenac 4'-hydroxylation with a Ki value of 16.3 µM, and it exhibited mechanism-based inhibition of CYP2C19-catalyzed [S]-mephenytoin 4'-hydroxylation (Ki, 3.7 µM; kinact, 0.102 min-1), CYP2C8-catalyzed amodiaquine N-deethylation (Ki, 10.7 µM; kinact, 0.082 min-1), and CYP3A4-catalyzed midazolam 1'-hydroxylation (Ki, 23.0 µM; kinact, 0.050 min-1) in human liver microsomes. Fargesin negligibly inhibited CYP1A2-catalyzed phenacetin O-deethylation, CYP2A6-catalyzed coumarin 7-hydroxylation, CYP2B6-catalyzed bupropion hydroxylation, and CYP2D6-catalyzed bufuralol 1'-hydroxylation at 100 µM in human liver microsomes. Dimethyllirioresinol weakly inhibited CYP2C19 and CYP2C8 with IC50 values of 55.1 and 85.0 µM, respectively, without inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, and CYP3A4 activities at 100 µM. Epimagnolin A, eudesmin, and magnolin showed no the reversible and time-dependent inhibition of eight major CYP activities at 100 µM in human liver microsomes. These in vitro results suggest that it is necessary to investigate the potentials of in vivo fargesin-drug interaction with CYP2C8, CYP2C9, CYP2C19, and CYP3A4 substrates.
[Mh] Termos MeSH primário: Benzodioxóis/farmacologia
Inibidores das Enzimas do Citocromo P-450/farmacocinética
Furanos/farmacologia
Lignanas/farmacocinética
Microssomos Hepáticos/efeitos dos fármacos
[Mh] Termos MeSH secundário: Sistema Enzimático do Citocromo P-450/metabolismo
Seres Humanos
Lignanas/química
Lignanas/farmacologia
Microssomos Hepáticos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzodioxoles); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Furans); 0 (Lignans); 31008-18-1 (magnolin); 526-06-7 (eudesmin); 9035-51-2 (Cytochrome P-450 Enzyme System); GR9853GI71 (fargesin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180202
[Lr] Data última revisão:
180202
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE


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[PMID]:29250980
[Au] Autor:Lee SH; Kim HY; Back SY; Han HK
[Ad] Endereço:a College of Pharmacy , Dongguk University-Seoul , Goyang , Korea.
[Ti] Título:Piperine-mediated drug interactions and formulation strategy for piperine: recent advances and future perspectives.
[So] Source:Expert Opin Drug Metab Toxicol;14(1):43-57, 2018 Jan.
[Is] ISSN:1744-7607
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Piperine has various pharmacological effects and can modulate the functional activity of metabolic enzymes and drug transporters. Consequently, there is a great interest in the application of piperine as an alternative medicine or bioavailability enhancer. Areas covered: This review deals with the effects of piperine on metabolizing enzymes and drug transporters. It provides the readers with an update on transporter-mediated and also metabolic enzyme-mediated piperine-drug interactions, with emphasis on its in vivo implications. This article also encompasses recent advances in the formulation approaches and technologies for optimizing the delivery of piperine. Expert opinion: Piperine can influence the pharmacokinetics of coadministered drugs, which may result in a therapeutically beneficial or adverse effect. Given that piperine inhibits or stimulates the activity of metabolic enzymes and transporters depending on the treatment conditions, the clinical significance of piperine-drug interactions should be assessed by varying the dose, dosing frequency, and the duration of treatment. In particular, better understanding the clinical relevance of piperine-drug interactions based on long-term assessments will provide a strong basis for the feasibility and applicability of piperine as a bioenhancer or a health-promoting agent. The development of effective formulations is also critical to facilitate the therapeutic applications of piperine.
[Mh] Termos MeSH primário: Alcaloides/administração & dosagem
Benzodioxóis/administração & dosagem
Inibidores das Enzimas do Citocromo P-450/administração & dosagem
Sistemas de Liberação de Medicamentos
Piperidinas/administração & dosagem
Alcamidas Poli-Insaturadas/administração & dosagem
[Mh] Termos MeSH secundário: Alcaloides/farmacologia
Animais
Benzodioxóis/farmacologia
Disponibilidade Biológica
Química Farmacêutica/métodos
Inibidores das Enzimas do Citocromo P-450/farmacologia
Relação Dose-Resposta a Droga
Interações Medicamentosas
Seres Humanos
Proteínas de Membrana Transportadoras/efeitos dos fármacos
Proteínas de Membrana Transportadoras/metabolismo
Piperidinas/farmacologia
Alcamidas Poli-Insaturadas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Alkaloids); 0 (Benzodioxoles); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Membrane Transport Proteins); 0 (Piperidines); 0 (Polyunsaturated Alkamides); U71XL721QK (piperine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180101
[Lr] Data última revisão:
180101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171219
[St] Status:MEDLINE
[do] DOI:10.1080/17425255.2018.1418854


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[PMID]:29202402
[Au] Autor:Park SY; Oh YJ; Lho Y; Jeong JH; Liu KH; Song J; Kim SH; Ha E; Seo YH
[Ad] Endereço:College of Pharmacy, Keimyung University, Daegu 704-701, South Korea.
[Ti] Título:Design, synthesis, and biological evaluation of a series of resorcinol-based N-benzyl benzamide derivatives as potent Hsp90 inhibitors.
[So] Source:Eur J Med Chem;143:390-401, 2018 Jan 01.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that is responsible for the stabilization and maturation of many oncogenic proteins. Therefore, Hsp90 has emerged as an attractive target in the field of cancer chemotherapy. In this study, we report the design, synthesis, and biological evaluation of a series of Hsp90 inhibitors. In particular, compound 30f shows a significant Hsp90α inhibitory activity with IC value of 5.3 nM and an excellent growth inhibition with GI value of 0.42 µM against non-small cell lung cancer cells, H1975. Compound 30f effectively reduces the expression levels of Hsp90 client proteins including Her2, EGFR, Met, Akt, and c-Raf. Consequently, compound 30f promotes substantial cleavages of PARP, Caspase 3, and Caspase 8, indicating that 30f induces cancer cell death via apoptotic pathway. Moreover, cytochrome P450 assay indicates that compound 30f has weak inhibitory effect on the activities of five major P450 isoforms (IC > 5 µM for 1A2, 2C9, 2C19, 2D6, and 3A), suggesting that clinical interactions between 30f and the substrate drugs of the five major P450 isoforms are not expected. Compound 30f also inhibits the tumor growth in a mouse xenograft model bearing subcutaneous H1975 without noticeable abnormal behavior and body weight changes. The immunostaining and western immunoblot analysis of EGFR, Met, Akt in xenograft tissue sections of tumor further demonstrate a good agreement with the in vitro results.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Benzamidas/farmacologia
Inibidores das Enzimas do Citocromo P-450/farmacologia
Desenho de Drogas
Proteínas de Choque Térmico HSP90/antagonistas & inibidores
Resorcinóis/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/síntese química
Antineoplásicos/química
Benzamidas/síntese química
Benzamidas/química
Proliferação Celular/efeitos dos fármacos
Inibidores das Enzimas do Citocromo P-450/síntese química
Inibidores das Enzimas do Citocromo P-450/química
Sistema Enzimático do Citocromo P-450/metabolismo
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Proteínas de Choque Térmico HSP90/metabolismo
Seres Humanos
Masculino
Camundongos Endogâmicos NOD
Camundongos SCID
Estrutura Molecular
Neoplasias Experimentais/tratamento farmacológico
Neoplasias Experimentais/metabolismo
Neoplasias Experimentais/patologia
Resorcinóis/química
Relação Estrutura-Atividade
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Benzamides); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (HSP90 Heat-Shock Proteins); 0 (Resorcinols); 6X80438640 (benzamide); 9035-51-2 (Cytochrome P-450 Enzyme System); YUL4LO94HK (resorcinol)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180101
[Lr] Data última revisão:
180101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE


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[PMID]:29202738
[Au] Autor:Schink M; Dehus O
[Ad] Endereço:Helixor Heilmittel GmbH, 72348, Rosenfeld, Germany. mschink@helixor.de.
[Ti] Título:Effects of mistletoe products on pharmacokinetic drug turnover by inhibition and induction of cytochrome P450 activities.
[So] Source:BMC Complement Altern Med;17(1):521, 2017 Dec 04.
[Is] ISSN:1472-6882
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: European mistletoe (Viscum album) products used in cancer therapy are frequently combined with other anti-cancer-drugs. Hence, potential herb-drug interactions have become a major safety concern in mistletoe therapy. METHODS: Three European mistletoe products (Helixor® A, Helixor® M and Helixor® P from mistletoe grown on firs, apple trees and pines, respectively) were tested for inhibition of nine major cytochrome P450 (CYP) isoenzymes in a test system using pooled human liver microsomes and for induction of five CYP isoforms in human hepatocytes cultivated in vitro according to the relevant guideline. RESULTS: Major inhibition did not occur in any of the CYP marker reactions. For some CYP isoenzymes, a minor or intermediate inhibition could be observed, but without dose effect relationship. Induction activity (≥ 1.5-fold increase) was not found with any of the three mistletoe products. CONCLUSION: Since no induction capacity was found and major inhibition above 50% did not occur even with the highest concentration used, which is approximately 100,000-fold higher than the clinically relevant dose in plasma, a clinically relevant herb-drug interaction is not expected for Helixor® A, M, and P.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Inibidores das Enzimas do Citocromo P-450/farmacologia
Sistema Enzimático do Citocromo P-450/efeitos dos fármacos
Erva-de-Passarinho
Extratos Vegetais/farmacologia
[Mh] Termos MeSH secundário: Sistema Enzimático do Citocromo P-450/metabolismo
Feminino
Hepatócitos/efeitos dos fármacos
Seres Humanos
Masculino
Microssomos Hepáticos/efeitos dos fármacos
Microssomos Hepáticos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Plant Extracts); 75882-01-8 (Helixor); 9035-51-2 (Cytochrome P-450 Enzyme System)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171220
[Lr] Data última revisão:
171220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171206
[St] Status:MEDLINE
[do] DOI:10.1186/s12906-017-2028-1


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[PMID]:29022838
[Au] Autor:Amsden JR; Gubbins PO
[Ad] Endereço:a Department of Pharmacy Practice , Butler University College of Pharmacy and Health Sciences , Indianapolis , IN , USA.
[Ti] Título:Pharmacogenomics of triazole antifungal agents: implications for safety, tolerability and efficacy.
[So] Source:Expert Opin Drug Metab Toxicol;13(11):1135-1146, 2017 Nov.
[Is] ISSN:1744-7607
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Triazole antifungal agents are prescribed to treat invasive fungal infections in neutropenic and non-neutropenic patients. These antifungal agents are substrates and inhibitors of cytochrome P450 (CYP). Genetic polymorphisms in CYP2C9, CYP2C19 and CYP3A5 can lead to large population-specific variations in drug efficacy and safety, optimal dosing, or contribute to drug interactions associated with this class. Areas covered: This manuscript reviews the pharmacogenomics (i.e. the influence of genetics on drug disposition) of triazole antifungal agents related to their CYP-mediated metabolism and summarizes their implications on triazole efficacy, safety, and tolerability. A search of English language original research, and scholarly reviews describing the pharmacogenomics of triazole antifungal agents and their impact on drug efficacy, safety, and tolerability published from 1980 to present was undertaken using PubMed. Expert opinion: Currently studies demonstrating the pharmacogenomic influences on itraconazole, posaconazole and isavuconazole are minimal and limited to their inhibitory effects on CYP3A4 in expressors of CYP3A5 variants. Conversely, there are significant pharmacogenomic considerations for voriconazole because it interacts with several polymorphic CYPs, most notably CYP2C19. Pharmacogenomics of CYP2C9 do not appear to effect fluconazole safety and efficacy. However, genetic polymorphisms may influence its drug interactions but this needs further study.
[Mh] Termos MeSH primário: Antifúngicos/uso terapêutico
Farmacogenética
Triazóis/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Antifúngicos/administração & dosagem
Antifúngicos/efeitos adversos
Inibidores das Enzimas do Citocromo P-450/administração & dosagem
Inibidores das Enzimas do Citocromo P-450/efeitos adversos
Inibidores das Enzimas do Citocromo P-450/uso terapêutico
Sistema Enzimático do Citocromo P-450/efeitos dos fármacos
Sistema Enzimático do Citocromo P-450/genética
Sistema Enzimático do Citocromo P-450/metabolismo
Relação Dose-Resposta a Droga
Interações Medicamentosas
Seres Humanos
Polimorfismo Genético
Triazóis/administração & dosagem
Triazóis/efeitos adversos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antifungal Agents); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Triazoles); 9035-51-2 (Cytochrome P-450 Enzyme System)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171013
[St] Status:MEDLINE
[do] DOI:10.1080/17425255.2017.1391213


  9 / 5278 MEDLINE  
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[PMID]:28960974
[Au] Autor:Sun R; Shi F; Liu K; Fu L; Tian C; Yang Y; Tallman KA; Porter NA; Yang J
[Ad] Endereço:State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine , Beijing 102206, China.
[Ti] Título:A Chemoproteomic Platform To Assess Bioactivation Potential of Drugs.
[So] Source:Chem Res Toxicol;30(10):1797-1803, 2017 Oct 16.
[Is] ISSN:1520-5010
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Reactive metabolites (RM) formed from bioactivation of drugs can covalently modify liver proteins and cause mechanism-based inactivation of major cytochrome P450 (CYP450) enzymes. Risk of bioactivation of a test compound is routinely examined as part of lead optimization efforts in drug discovery. Here we described a chemoproteomic platform to assess in vitro and in vivo bioactivation potential of drugs. This platform enabled us to determine reactivity of thousands of proteomic cysteines toward RMs of diclofenac formed in human liver microsomes and living animals. We pinpointed numerous reactive cysteines as the targets of RMs of diclofenac, including the active (heme-binding) sites on several key CYP450 isoforms (1A2, 2E1 and 3A4 for human, 2C39 and 3A11 for mouse). This general platform should be applied to other drugs, drug candidates, and xenobiotics with potential hepatoxicity, including environmental organic substances, bioactive natural products, and traditional Chinese medicine.
[Mh] Termos MeSH primário: Inibidores das Enzimas do Citocromo P-450/efeitos adversos
Sistema Enzimático do Citocromo P-450/metabolismo
Diclofenaco/efeitos adversos
Microssomos Hepáticos/efeitos dos fármacos
Proteômica
Xenobióticos/efeitos adversos
[Mh] Termos MeSH secundário: Animais
Inibidores das Enzimas do Citocromo P-450/metabolismo
Diclofenaco/metabolismo
Relação Dose-Resposta a Droga
Seres Humanos
Camundongos
Microssomos Hepáticos/metabolismo
Xenobióticos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Xenobiotics); 144O8QL0L1 (Diclofenac); 9035-51-2 (Cytochrome P-450 Enzyme System)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170930
[St] Status:MEDLINE
[do] DOI:10.1021/acs.chemrestox.7b00183


  10 / 5278 MEDLINE  
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[PMID]:28941798
[Au] Autor:Tang S; Chen A; Zhou X; Zeng L; Liu M; Wang X
[Ad] Endereço:Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
[Ti] Título:Assessment of the inhibition risk of shikonin on cytochrome P450 via cocktail inhibition assay.
[So] Source:Toxicol Lett;281:74-83, 2017 Nov 05.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Shikonin is a naphthoquinone pigment extracted from roots of Lithospermum erythrorhizon Sieb. et Zucc. (Boraginaceae), and possesses various pharmaceutical activities, such as anti-inflammation and anti-cancer effects. In addition, shikonin as a natural red colorant for food garnishment and cosmetics ingredient is widely used in the world. However, the inhibition risk of shikonin on cytochrome P450 (CYP) remains unclear. The aim of this study was to investigate the potential inhibition of shikonin against CYP1A2, CYP2B1/6, CYP2C9/11, CYP2D1/6, CYP2E1 and CYP3A2/4 activities in human and rat liver microsomes through cocktail approach in vitro. The results demonstrated that shikonin exhibited no time-dependent inhibition of CYP activities. In human liver microsomes, shikonin was not only a mixed inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2D6 and CYP3A4, but also a competitive inhibitor of CYP2E1, with K values no more than 7.72µM. In rat liver microsomes, shikonin also exhibited the mixed inhibition on CYP1A2, CYP2B1, CYP2C11, CYP2D1, and the competitive inhibition on CYP2E1. Interestingly, shikonin presented an atypical kinetic inhibition of CYP3A2-mediated midazolam 1-hydroxylation in rats. In conclusion, the relatively low K values of shikonin would have a high risk potential to cause the possible toxicity, especially drug-drug or food-drug interactions based on the potent inhibition of CYP enzymes.
[Mh] Termos MeSH primário: Inibidores das Enzimas do Citocromo P-450/toxicidade
Sistema Enzimático do Citocromo P-450/metabolismo
Microssomos Hepáticos/efeitos dos fármacos
Naftoquinonas/toxicidade
[Mh] Termos MeSH secundário: Animais
Sistema Enzimático do Citocromo P-450/genética
Interações Medicamentosas
Interações Alimento-Droga
Seres Humanos
Hidroxilação
Concentração Inibidora 50
Masculino
Microssomos Hepáticos/enzimologia
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Naphthoquinones); 3IK6592UBW (shikonin); 9035-51-2 (Cytochrome P-450 Enzyme System)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170925
[St] Status:MEDLINE



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