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Pesquisa : D27.505.389.249 [Categoria DeCS]
Referências encontradas : 61 [refinar]
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[PMID]:28601433
[Au] Autor:Bacqueville D; Jacques C; Duprat L; Jamin EL; Guiraud B; Perdu E; Bessou-Touya S; Zalko D; Duplan H
[Ad] Endereço:Pierre Fabre Dermo-cosmétique, Service Pharmacologie Division 2 et Pharmacocinétique Cutané, Département Pharmacologie, Centre R&D Pierre Fabre, 3 avenue Hubert Curien, Toulouse, France. Electronic address: daniel.bacqueville@pierre-fabre.com.
[Ti] Título:Characterization of xenobiotic metabolizing enzymes of a reconstructed human epidermal model from adult hair follicles.
[So] Source:Toxicol Appl Pharmacol;329:190-201, 2017 Aug 15.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In this study, a comprehensive characterization of xenobiotic metabolizing enzymes (XMEs) based on gene expression and enzyme functionality was made in a reconstructed skin epidermal model derived from the outer root sheath (ORS) of hair follicles (ORS-RHE). The ORS-RHE model XME gene profile was consistent with native human skin. Cytochromes P450 (CYPs) consistently reported to be detected in native human skin were also present at the gene level in the ORS-RHE model. The highest Phase I XME gene expression levels were observed for alcohol/aldehyde dehydrogenases and (carboxyl) esterases. The model was responsive to the CYP inducers, 3-methylcholanthrene (3-MC) and ß-naphthoflavone (ßNF) after topical and systemic applications, evident at the gene and enzyme activity level. Phase II XME levels were generally higher than those of Phase I XMEs, the highest levels were GSTs and transferases, including NAT1. The presence of functional CYPs, UGTs and SULTs was confirmed by incubating the models with 7-ethoxycoumarin, testosterone, benzo(a)pyrene and 3-MC, all of which were rapidly metabolized within 24h after topical application. The extent of metabolism was dependent on saturable and non-saturable metabolism by the XMEs and on the residence time within the model. In conclusion, the ORS-RHE model expresses a number of Phase I and II XMEs, some of which may be induced by AhR ligands. Functional XME activities were also demonstrated using systemic or topical application routes, supporting their use in cutaneous metabolism studies. Such a reproducible model will be of interest when evaluating the cutaneous metabolism and potential toxicity of innovative dermo-cosmetic ingredients.
[Mh] Termos MeSH primário: Sistema Enzimático do Citocromo P-450/biossíntese
Folículo Piloso/enzimologia
Queratinócitos/enzimologia
Xenobióticos/metabolismo
[Mh] Termos MeSH secundário: Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo
Células Cultivadas
Indutores das Enzimas do Citocromo P-450/farmacologia
Sistema Enzimático do Citocromo P-450/genética
Indução Enzimática
Glutationa Transferase/biossíntese
Glutationa Transferase/genética
Folículo Piloso/citologia
Folículo Piloso/efeitos dos fármacos
Seres Humanos
Isoenzimas
Queratinócitos/efeitos dos fármacos
Cinética
Ligantes
Desentoxicação Metabólica Fase I
Desintoxicação Metabólica Fase II
Receptores de Hidrocarboneto Arílico/agonistas
Receptores de Hidrocarboneto Arílico/metabolismo
Especificidade por Substrato
Sulfotransferases/biossíntese
Sulfotransferases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AHR protein, human); 0 (Basic Helix-Loop-Helix Transcription Factors); 0 (Cytochrome P-450 Enzyme Inducers); 0 (Isoenzymes); 0 (Ligands); 0 (Receptors, Aryl Hydrocarbon); 0 (Xenobiotics); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 2.5.1.18 (Glutathione Transferase); EC 2.8.2.- (Sulfotransferases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170731
[Lr] Data última revisão:
170731
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170612
[St] Status:MEDLINE


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[PMID]:28302129
[Au] Autor:Guo J; Gao Y; Cao X; Zhang J; Chen W
[Ad] Endereço:Food Science Department, College of Biochemical Engineering, Beijing Union University, Fatou west 18#, Chaoyang District, Beijing, 100023, People's Republic of China.
[Ti] Título:Cholesterol-lowing effect of taurine in HepG2 cell.
[So] Source:Lipids Health Dis;16(1):56, 2017 Mar 16.
[Is] ISSN:1476-511X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: A number of studies indicate that taurine promotes cholesterol conversion to bile acids by upregulating CYP7A1 gene expression. Few in vitro studies are concerned the concentration change of cholesterol and its product of bile acids, and the molecular mechanism of CYP7A1 induction by taurine. METHODS: The levels of intracellular total cholesterol (TC), free cholesterol (FC), cholesterol ester (EC), total bile acids (TBA) and medium TBA were determined after HepG2 cells were cultured for 24/48 h in DMEM supplemented with taurine at the final concentrations of 1/10/20 mM respectively. The protein expressions of CYP7A1, MEK1/2, c-Jun, p-c-Jun and HNF-4α were detected. RESULTS: Taurine significantly reduced cellular TC and FC in dose -and time-dependent ways, and obviously increased intracellular/medium TBA and CYP7A1 expressions. There was no change in c-Jun expression, but the protein expressions of MEK1/2 and p-c-Jun were increased at 24 h and inhibited at 48 h by 20 mM taurine while HNF4α was induced after both of the 24 h and 48 h treatment. CONCLUSION: Taurine could enhance CYP7A1 expression by inducing HNF4α and inhibiting MEK1/2 and p-c-Jun expressions to promote intracellular cholesterol metabolism.
[Mh] Termos MeSH primário: Anticolesterolemiantes/farmacologia
Colesterol/metabolismo
Taurina/farmacologia
[Mh] Termos MeSH secundário: Ácidos e Sais Biliares/metabolismo
Colesterol 7-alfa-Hidroxilase/genética
Colesterol 7-alfa-Hidroxilase/metabolismo
Indutores das Enzimas do Citocromo P-450/farmacologia
Avaliação Pré-Clínica de Medicamentos
Indução Enzimática/efeitos dos fármacos
Células Hep G2
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticholesteremic Agents); 0 (Bile Acids and Salts); 0 (Cytochrome P-450 Enzyme Inducers); 1EQV5MLY3D (Taurine); 97C5T2UQ7J (Cholesterol); EC 1.14.14.23 (CYP7A1 protein, human); EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170612
[Lr] Data última revisão:
170612
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170318
[St] Status:MEDLINE
[do] DOI:10.1186/s12944-017-0444-3


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[PMID]:28177134
[Au] Autor:Li TY; Liu W; Chen K; Liang SY; Liu F
[Ad] Endereço:Pharmacy Department, Peking University Third Hospital, Beijing, China.
[Ti] Título:The influence of combination use of CYP450 inducers on the pharmacokinetics of voriconazole: a systematic review.
[So] Source:J Clin Pharm Ther;42(2):135-146, 2017 Apr.
[Is] ISSN:1365-2710
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:WHAT IS KNOWN AND OBJECTIVES: Voriconazole is a triazole antifungal agent and is extensively metabolized via cytochrome P450 (CYP450); therefore, special precautions need to be taken when co-administered with a known CYP450 inducer, which may lead to treatment failure. The influence of some CYP450 inducers on the pharmacokinetics of voriconazole has been described in previous studies, but a systematic review was lacking. In this study, we carried out a systematic review to assess the influence of CYP450 inducers on the pharmacokinetic (PK) parameters of voriconazole. METHODS: Pubmed, Embase, Cochrane Library, Clinicaltrials.gov and three Chinese databases (CNKI, CBM and WanFang) were searched through January 2016. Interventional and observational studies comparing the PK parameters of voriconazole used alone or with CYP450 inducers in healthy volunteers and patients were included. The outcomes included were the area under the plasma concentration-time curve (AUC), peak plasma concentrations (C ) and trough plasma concentrations (C ). The quality of the included studies was assessed using Cochrane's risk of bias tool, Newcastle-Ottawa Scale (NOS) and a modified risk of bias tool for pharmacokinetic before-and-after studies. RESULTS AND DISCUSSION: Sixteen studies were included in this review: three randomized controlled trials (RCTs), five single-arm before-after studies (SBAs), six cohort studies and two case reports. All studies except case reports had moderate to high quality. Of the 11 inducers reviewed, efavirenz, ritonavir (chronic use), phenytoin, rifampin and rifabutin significantly decreased mean AUC and C of voriconazole; St John's wort significantly decreased only mean AUC; rifampin, rifabutin, phenobarbital and carbamazepine significantly decreased mean C . Etravirine and Ginkgo biloba did not reveal any such influence. The influence of glucocorticoids may depend on its type and dose. WHAT IS NEW AND CONCLUSIONS: To conclude, the combination use of high-dose efavirenz, high-dose ritonavir, St John's wort, rifampin, phenobarbital, or carbamazepine with voriconazole is contraindicated as instructed in the drug label. Low-dose efavirenz, low-dose ritonavir, rifabutin and phenytoin may be used together with voriconazole provided TDM and dose adjustment of voriconazole. Moreover, this study shows there is low risk of drug-drug interactions when voriconazole is co-administered with etravirine or G. biloba; however, whether the use of glucocorticoids has a clinically significant effect on voriconazole still requires more evidence. This study also highlights the lack of clinical studies and future high-quality studies assessing the influence of CYP450 inducers on voriconazole. PK parameters and dosing optimization should be designed to provide a more definitive answer regarding the necessity of TDM and the recommendations for dose adjustment of voriconazole.
[Mh] Termos MeSH primário: Antifúngicos/farmacocinética
Indutores das Enzimas do Citocromo P-450/farmacologia
Voriconazol/farmacocinética
[Mh] Termos MeSH secundário: Citocromo P-450 CYP2C19/fisiologia
Citocromo P-450 CYP2C9/fisiologia
Interações Medicamentosas
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antifungal Agents); 0 (Cytochrome P-450 Enzyme Inducers); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.14.1 (Cytochrome P-450 CYP2C19); JFU09I87TR (Voriconazole)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170209
[St] Status:MEDLINE
[do] DOI:10.1111/jcpt.12493


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[PMID]:27889832
[Au] Autor:Dymond AW; So K; Martin P; Huang Y; Severin P; Mathews D; Lisbon E; Mariani G
[Ad] Endereço:AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
[Ti] Título:Effects of cytochrome P450 (CYP3A4 and CYP2C19) inhibition and induction on the exposure of selumetinib, a MEK1/2 inhibitor, in healthy subjects: results from two clinical trials.
[So] Source:Eur J Clin Pharmacol;73(2):175-184, 2017 Feb.
[Is] ISSN:1432-1041
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Two phase I, open-label trials in healthy subjects assessed whether co-administration with CYP3A4/CYP2C19 inhibitors, itraconazole/fluconazole (study A), or CYP3A4 inducer, rifampicin (study B), affects the exposure, safety/tolerability and pharmacokinetics of selumetinib and its metabolite N-desmethyl selumetinib. METHODS: In study A (n = 26), subjects received a single dose of selumetinib 25 mg and, after 4 days of washout, were randomized to treatment 1 (itraconazole 200 mg twice daily on days 1-11) or treatment 2 (fluconazole 400 mg on day 1 then 200 mg/day on days 2-11) plus co-administration of single-dose selumetinib 25 mg on day 8 (selumetinib staggered 4 h after itraconazole/fluconazole dose); Twenty-one days after discharge/washout, subjects received the alternate treatment. In study B (n = 22), subjects received a single dose of selumetinib 75 mg (day 1) then rifampicin 600 mg/day (days 4-14) plus a single dose of selumetinib 75 mg on day 12. Pharmacokinetic analysis and safety assessments were performed. RESULTS: Selumetinib co-administered with itraconazole, fluconazole (selumetinib staggered 4 h after itraconazole/fluconazole dose), or rifampicin was well tolerated. Selumetinib exposure was higher when co-administered with itraconazole or fluconazole (area under the plasma concentration-time curve (AUC) increased by 49 and 53%, respectively; maximum plasma concentration (C ) increased by 19 and 26%, respectively) but lower when co-dosed with rifampicin (AUC and C decreased by 51 and 26%, respectively) versus selumetinib dosed alone. Co-administration with itraconazole or rifampicin decreased N-desmethyl selumetinib AUC (11 and 55%, respectively), and C (25 and 18%, respectively), with fluconazole, AUC increased by 40%, but there was no effect on C . CONCLUSIONS: Co-administration of CYP3A4/CYP2C19 inhibitors will likely increase exposure to selumetinib, while CYP3A4 inducers will likely reduce its exposure.
[Mh] Termos MeSH primário: Benzimidazóis/farmacocinética
Inibidores do Citocromo P-450 CYP2C19/farmacologia
Inibidores do Citocromo P-450 CYP3A/farmacologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Benzimidazóis/sangue
Estudos Cross-Over
Citocromo P-450 CYP2C19/metabolismo
Citocromo P-450 CYP3A/metabolismo
Indutores das Enzimas do Citocromo P-450/farmacologia
Feminino
Fluconazol/farmacologia
Voluntários Saudáveis
Seres Humanos
Itraconazol/farmacologia
MAP Quinase Quinase Quinase 1/antagonistas & inibidores
MAP Quinase Quinase Quinase 2/antagonistas & inibidores
Masculino
Rifampina/farmacologia
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (AZD 6244); 0 (Benzimidazoles); 0 (Cytochrome P-450 CYP2C19 Inhibitors); 0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Cytochrome P-450 Enzyme Inducers); 304NUG5GF4 (Itraconazole); 8VZV102JFY (Fluconazole); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (CYP2C19 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2C19); EC 1.14.14.1 (Cytochrome P-450 CYP3A); EC 2.7.11.25 (MAP Kinase Kinase Kinase 1); EC 2.7.11.25 (MAP Kinase Kinase Kinase 2); VJT6J7R4TR (Rifampin)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170227
[Lr] Data última revisão:
170227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161128
[St] Status:MEDLINE
[do] DOI:10.1007/s00228-016-2153-7


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[PMID]:27819488
[Au] Autor:El-Sherbeni AA; El-Kadi AO
[Ad] Endereço:a Faculty of Pharmacy and Pharmaceutical Sciences , 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta , Edmonton , Alberta , Canada.
[Ti] Título:Microsomal cytochrome P450 as a target for drug discovery and repurposing.
[So] Source:Drug Metab Rev;49(1):1-17, 2017 Feb.
[Is] ISSN:1097-9883
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cytochrome P450 (P450) enzymes are ancient electron-transfer-chain system of remarkable biological importance. Microsomal P450 enzymes are the P450 attached to endoplasmic reticulum, which, in humans, are critical for body's defenses against xenobiotics by mediating their metabolism, and cell signaling by mediating arachidonic acid (AA) transformation to several potent bioactive molecules. Only recently, modulating P450-mediated AA metabolism has risen as a promising new drug target. This review presents the therapeutic potential of finding effective, selective and safe treatments targeting P450-mediated AA metabolism, and the several approaches that have been used to find these treatments; among which, our focus was on modulators of P450 activities. We detailed the efforts done to develop new molecular entities designed to modulate P450, and the more recent efforts tried to employ our previous knowledge on drug metabolism to repurpose old drugs with the capacity to alter P450-mediated drug metabolism to target AA metabolism. Because of the long recognition of P450 role in xenobiotic metabolism, several clinically approved agents were identified to alter P450 activity. Repurposing old drugs as P450 modulators can facilitate bringing treatments targeting P450-mediated AA metabolism to clinical trials. However, the capacity of the modulation of P450-derived AA metabolites of clinically approved drugs has to be systematically investigated and validated for their new use in humans.
[Mh] Termos MeSH primário: Sistema Enzimático do Citocromo P-450/efeitos dos fármacos
Descoberta de Drogas
Reposicionamento de Medicamentos
Microssomos/enzimologia
[Mh] Termos MeSH secundário: Ácido Araquidônico/metabolismo
Ácido Araquidônico/fisiologia
Indutores das Enzimas do Citocromo P-450/farmacologia
Inibidores das Enzimas do Citocromo P-450/farmacologia
Sistema Enzimático do Citocromo P-450/metabolismo
Sistema Enzimático do Citocromo P-450/fisiologia
Interações Medicamentosas
Epóxido Hidrolases/antagonistas & inibidores
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Cytochrome P-450 Enzyme Inducers); 0 (Cytochrome P-450 Enzyme Inhibitors); 27YG812J1I (Arachidonic Acid); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 3.3.2.- (Epoxide Hydrolases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170830
[Lr] Data última revisão:
170830
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161108
[St] Status:MEDLINE
[do] DOI:10.1080/03602532.2016.1257021


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[PMID]:27594525
[Au] Autor:Men L; Zhao Y; Lin H; Tang X; Yu Z
[Ad] Endereço:a College of Life Science, Dalian Nationalities University , Dalian , Liaoning Province , China.
[Ti] Título:Evaluation of the tissue distribution, excretion, and cytochrome P450 induction studies of a potential antitumor agent, TM-2, in animals using LC-MS/MS.
[So] Source:Xenobiotica;47(9):800-806, 2017 Sep.
[Is] ISSN:1366-5928
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:1. TM-2 is a promising novel semi-synthetic taxane derivative with greater antitumor activity especially against resistant tumors and lower toxicity compared with docetaxel. Information on distribution and excretion of the pharmaceutical in animals, as well as biochemical information relevant to potential drug interactions should normally be evaluated prior to human clinical trials. 2. The present study investigated the tissue distribution and excretion of TM-2 in animals following intravenous administration for further advancement of the molecule. The potential inductive effect of TM-2 on cytochrome P450 iso-enzymes CYP 3A1 in rats was also evaluated. 3. The tissue distribution study in mice showed that TM-2 was rapidly dispersed in the various tissues and peak concentration levels were achieved within 0.083-1 h. The highest concentration was detected in pancreas, followed by lung, kidney, spleen, heart and liver. TM-2 was mainly excreted in the feces via the bile (0.14% of the dose) and urinary excretion was minimal (0.007%). TM-2 increased CYP3A1 enzyme activities with time and dose dependence in rat liver microsome. 4. This important data serve as a useful resource to support further research of TM-2 and allow intelligent assessment of toxicology and in vivo activity testing performed in animals.
[Mh] Termos MeSH primário: Antineoplásicos/farmacocinética
Indutores das Enzimas do Citocromo P-450/farmacocinética
Sistema Enzimático do Citocromo P-450/metabolismo
Taxoides/farmacocinética
[Mh] Termos MeSH secundário: Animais
Cromatografia Líquida
Seres Humanos
Camundongos
Microssomos Hepáticos/metabolismo
Ratos
Espectrometria de Massas em Tandem
Distribuição Tecidual
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (13-(N-tert-butoxycarbonyl-3-isobutylisoserinoyl-4,10-diacetoxy-2-benzoyloxy-5-20-epoxy-1,13-dihydroxy-9-oxo-19-norcyclopropa(g)tax-11-ene); 0 (Antineoplastic Agents); 0 (Cytochrome P-450 Enzyme Inducers); 0 (Taxoids); 9035-51-2 (Cytochrome P-450 Enzyme System)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160906
[St] Status:MEDLINE
[do] DOI:10.1080/00498254.2016.1232446


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[PMID]:27878498
[Au] Autor:Il'nitskaya SI; Kaledin VI; Bogdanova LA; Morozkova TS; Kapustina VI; Perepechaeva ML; Grishanova AY
[Ad] Endereço:Institute of Cytology and Genetics, Siberian Division of the Russian Academy of Sciences, Novosibirsk, Russia. pathol@inbox.ru.
[Ti] Título:Stimulation of Diethylnitrosamine Metabolism Reduces Its General Toxic and Hepatocarcinogenic Effects.
[So] Source:Bull Exp Biol Med;162(1):98-101, 2016 Nov.
[Is] ISSN:1573-8221
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The general toxic and hepatocarcinogenic effects of diethylnitrosamine after stimulation of its metabolism with 1,4-bis[2-(3,5-dichloropyridyloxy)]-benzene (TCPOBOP) were studied. The hydroxylating activity of liver microsomes of C57Bl/6Mv mice towards p-nitrophenol increased more than 4-fold 3 days after injection of TCPOBOP. Injection of diethylnitrosamine 3 days after TCPOBOP caused a lesser body weight loss and decrease of food consumption in C57Bl/6Mv mice than in response to diethylnitrosamine without preinduction. Injection of diethylnitrosamine to suckling ICR mice after TCPOBOP induction of cytochrome P450 2e1 activity led to development of 2-fold lesser number of tumors and pretumorous nodes in the liver in comparison with animals injected with diethylnitrosamine without induction. These data indicated that metabolism stimulation reduced the general toxic and hepatocarcinogenic effects of diethylnitrosamine.
[Mh] Termos MeSH primário: Carcinogênese/efeitos dos fármacos
Indutores das Enzimas do Citocromo P-450/farmacologia
Dietilnitrosamina/metabolismo
Inativação Metabólica/efeitos dos fármacos
Neoplasias Hepáticas Experimentais/tratamento farmacológico
Piridinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Animais Lactentes
Peso Corporal/efeitos dos fármacos
Carcinogênese/metabolismo
Carcinogênese/patologia
Citocromo P-450 CYP2E1/metabolismo
Dietilnitrosamina/toxicidade
Fígado/efeitos dos fármacos
Fígado/enzimologia
Neoplasias Hepáticas Experimentais/induzido quimicamente
Neoplasias Hepáticas Experimentais/enzimologia
Neoplasias Hepáticas Experimentais/patologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Endogâmicos ICR
Microssomos Hepáticos/efeitos dos fármacos
Microssomos Hepáticos/enzimologia
Nitrofenóis/metabolismo
Carga Tumoral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 Enzyme Inducers); 0 (Nitrophenols); 0 (Pyridines); 3IQ78TTX1A (Diethylnitrosamine); 76150-91-9 (1,4-bis(2-(3,5-dichloropyridyloxy))benzene); EC 1.14.13.- (Cytochrome P-450 CYP2E1); Y92ZL45L4R (4-nitrophenol)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170207
[Lr] Data última revisão:
170207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161124
[St] Status:MEDLINE


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[PMID]:27800121
[Au] Autor:Sheweita SA; Wally M; Hassan M
[Ad] Endereço:Biotechnology Department, Institute of Graduate Studies & Research, Alexandria University, 163 El Horreya Avenue 21526, P.O. Box 832, Alexandria, Egypt.
[Ti] Título:Erectile Dysfunction Drugs Changed the Protein Expressions and Activities of Drug-Metabolising Enzymes in the Liver of Male Rats.
[So] Source:Oxid Med Cell Longev;2016:4970906, 2016.
[Is] ISSN:1942-0994
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Erectile dysfunction (ED) is a major health problem and is mainly associated with the persistent inability of men to maintain sufficient erection for satisfactory sexual performance. Millions of men are using sildenafil, vardenafil, and/or tadalafil for ED treatment. Cytochrome P450s (CYPs) play a central role in the metabolism of a wide range of xenobiotics as well as endogenous compounds. Susceptibility of individuals to the adverse effects of different drugs is mainly dependent on the expression of CYPs proteins. Therefore, changes in activities of phase I drug-metabolising enzymes [arylhydrocarbon hydroxylase (AHH), dimethylnitrosamine N-demethylase (DMN-dI), 7-ethoxycoumarin-O-deethylase (ECOD), and ethoxyresorufin-O-deethylase ((EROD)] and the protein expression of different CYPs isozymes (CYP1A2, CYP2E1, CYP2B1/2, CYP3A4, CYP2C23, and CYP2C6) were determined after treatment of male rats with either low or high doses of sildenafil (Viagra), tadalafil (Cialis), and/or vardenafil (Levitra) for 3 weeks. The present study showed that low doses of tadalafil and vardenafil increased DMN-dI activity by 32 and 23%, respectively. On the other hand, high doses of tadalafil, vardenafil, and sildenafil decreased such activity by 50, 56, and 52%, respectively. In addition, low doses of tadalafil and vardenafil induced the protein expression of CYP2E1. On the other hand, high doses of either tadalafil or sildenafil were more potent inhibitors to CYP2E1 expression than vardenafil. Moreover, low doses of both vardenafil and sildenafil markedly increased AHH activity by 162 and 247%, respectively, whereas high doses of tadalafil, vardenafil, and sildenafil inhibited such activity by 36, 49, and 57% and inhibited the EROD activity by 39, 49, and 33%, respectively. Low and high doses of tadalafil, vardenafil, and sildenafil inhibited the activity of NADPH-cytochrome c reductase as well as its protein expression. In addition, such drugs inhibited the expression of CYP B1/2 along with its corresponding enzyme marker ECOD activity. It is concluded that changes in the expression and activity of phase I drug-metabolising enzymes could change the normal metabolic pathways and might enhance the deleterious effects of exogenous as well as endogenous compounds.
[Mh] Termos MeSH primário: Indutores das Enzimas do Citocromo P-450/farmacologia
Inibidores das Enzimas do Citocromo P-450/farmacologia
Sistema Enzimático do Citocromo P-450/metabolismo
Disfunção Erétil/tratamento farmacológico
Fígado/efeitos dos fármacos
Inibidores da Fosfodiesterase 5/farmacologia
Citrato de Sildenafila/farmacologia
Tadalafila/farmacologia
Dicloridrato de Vardenafila/farmacologia
[Mh] Termos MeSH secundário: Animais
Indutores das Enzimas do Citocromo P-450/toxicidade
Inibidores das Enzimas do Citocromo P-450/toxicidade
Relação Dose-Resposta a Droga
Interações Medicamentosas
Isoenzimas
Fígado/enzimologia
Masculino
Desentoxicação Metabólica Fase I
Inibidores da Fosfodiesterase 5/toxicidade
Ratos
Medição de Risco
Citrato de Sildenafila/toxicidade
Tadalafila/toxicidade
Dicloridrato de Vardenafila/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 Enzyme Inducers); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Isoenzymes); 0 (Phosphodiesterase 5 Inhibitors); 5O8R96XMH7 (Vardenafil Dihydrochloride); 742SXX0ICT (Tadalafil); 9035-51-2 (Cytochrome P-450 Enzyme System); BW9B0ZE037 (Sildenafil Citrate)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170313
[Lr] Data última revisão:
170313
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161102
[St] Status:MEDLINE


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[PMID]:27751854
[Au] Autor:Lin PP; Li XN; Yuan F; Chen WL; Yang MJ; Xu HR
[Ad] Endereço:Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
[Ti] Título:Evaluation of the in vitro and in vivo metabolic pathway and cytochrome P450 inhibition/induction profile of Huperzine A.
[So] Source:Biochem Biophys Res Commun;480(2):248-253, 2016 Nov 11.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Huperzine A (HupA), one of the reversible and selective acetylcholinesterase inhibitors derived from Chinese herb Huperzia Serrata, possesses affirmative action of ameliorating cognitive dysfunction of Alzheimer's disease. Up to now, the effects of HupA on human cytochrome P450s (CYPs) have not been fully elucidated. The purpose of the present study was to clarify the metabolic pathway of HupA in vitro and in vivo, and to evaluate the CYPs inhibition/induction profile of HupA in vitro. The catalytic activity of CYP enzymes (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4) was measured by the quantification of specific enzyme substrates using validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods. The in vivo metabolic pathway evaluation was performed in an open, single-dose pharmacokinetic study of HupA in fourteen elderly subjects, with urine collecting at certain intervals. In human liver microsomes, HupA (10 ng/mL) was not metabolized within 90 min, and it showed negligible inhibition against these CYP isoforms within 0.2-100 ng/mL. In human liver hepatocytes, the activities of CYP1A2 and CYP3A4 were not significantly altered when incubated at 2 or 20 ng/mL of HupA. After oral administration of 0.1 mg HupA, the total proportion of HupA excreted through urine was relatively high, accounting to 35± 9% at the limited time period of 48 h. These results suggest that HupA is substantially excreted by kidney unchanged rather than metabolized by human liver, and is unlikely to cause clinically relevant drug-drug interaction (DDI) when co-administrated with drugs that are metabolized by CYP isoenzyme system.
[Mh] Termos MeSH primário: Alcaloides/farmacologia
Inibidores das Enzimas do Citocromo P-450/farmacologia
Sistema Enzimático do Citocromo P-450/metabolismo
Microssomos Hepáticos/efeitos dos fármacos
Sesquiterpenos/farmacologia
[Mh] Termos MeSH secundário: Idoso
Alcaloides/farmacocinética
Alcaloides/urina
Indutores do Citocromo P-450 CYP1A2/farmacologia
Indutores do Citocromo P-450 CYP3A/farmacologia
Indutores das Enzimas do Citocromo P-450/farmacologia
Inibidores das Enzimas do Citocromo P-450/urina
Estabilidade de Medicamentos
Feminino
Hepatócitos/efeitos dos fármacos
Hepatócitos/metabolismo
Seres Humanos
Inativação Metabólica
Rim/efeitos dos fármacos
Rim/metabolismo
Masculino
Microssomos Hepáticos/metabolismo
Meia-Idade
Sesquiterpenos/farmacocinética
Sesquiterpenos/urina
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Alkaloids); 0 (Cytochrome P-450 CYP1A2 Inducers); 0 (Cytochrome P-450 CYP3A Inducers); 0 (Cytochrome P-450 Enzyme Inducers); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Sesquiterpenes); 0111871I23 (huperzine A); 9035-51-2 (Cytochrome P-450 Enzyme System)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170613
[Lr] Data última revisão:
170613
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161030
[St] Status:MEDLINE


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[PMID]:27550199
[Au] Autor:Ogasawara A; Torimoto N; Tsuda N; Aohara F; Ohashi R; Yamada Y; Taniguchi H
[Ad] Endereço:Advanced Drug Research Laboratories, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda-shi, Saitama 335-8505, Japan;.
[Ti] Título:New Screening Criteria Setting on Evaluation of Cytochrome P450 Induction Using HepaRG Cells with Multiplex Branched DNA Technologies in Early Drug Discovery.
[So] Source:Drug Metab Lett;10(3):152-160, 2016.
[Is] ISSN:1874-0758
[Cp] País de publicação:United Arab Emirates
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Cytochrome P450 (CYP) enzymes are induced by some therapeutic drugs, leading to interactions reducing drug plasma concentrations. Recently, an assessment of CYP induction using messenger RNA (mRNA) levels has shown advantages over measurement of enzymatic activity; it has a larger dynamic range of induction and enables us to measure the intrinsic induction potential of time-dependent CYP inhibitors. In order to minimize the late-stage attrition of new chemical entities (NCE), it is important to evaluate CYP induction potency at mRNA levels in the early stage of drug development. OBJECTIVES: The aim of this study is to establish a new screening method to evaluate induction potency of CYP1A2, CYP2B6, and CYP3A4 at mRNA levels. METHODS: QuantiGene Plex 2.0 Assay using HepaRG cells. RESULTS: The results from our new CYP induction assay system corresponded well to the already reported results obtained by using human hepatocytes. The induction potency was evaluated by calculating the concentration of test compounds that gives 10% of positive control response (R10), which is measurable even when full dose-response curves cannot be obtained. Compared with the evaluation of CYP induction in human hepatocytes, the response at R10 in HepaRG cells suggested the possibility of exhibiting induction potency for corresponding CYPs. Interestingly, the results with our in-house 109 compounds showed that several compounds induced CYP1A2 or CYP2B6 expression without upregulation of CYP3A4. CONCLUSION: Our developed assay system, as well as the R10 value, is useful for evaluating the CYP induction potency of NCE in early drug discovery.
[Mh] Termos MeSH primário: Desenho de Drogas
Indução Enzimática/efeitos dos fármacos
Hepatócitos/efeitos dos fármacos
Fígado/efeitos dos fármacos
[Mh] Termos MeSH secundário: Linhagem Celular
Citocromo P-450 CYP1A2/biossíntese
Citocromo P-450 CYP1A2/genética
Citocromo P-450 CYP2B6/biossíntese
Citocromo P-450 CYP2B6/genética
Citocromo P-450 CYP3A/biossíntese
Citocromo P-450 CYP3A/genética
Indutores das Enzimas do Citocromo P-450/farmacologia
Descoberta de Drogas/métodos
Hepatócitos/enzimologia
Seres Humanos
Fígado/enzimologia
RNA Mensageiro/metabolismo
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 Enzyme Inducers); 0 (RNA, Messenger); 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 CYP3A)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160824
[St] Status:MEDLINE



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