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[PMID]:28735742
[Au] Autor:Barreto A; Luis LG; Soares AMVM; Paíga P; Santos LHMLM; Delerue-Matos C; Hylland K; Loureiro S; Oliveira M
[Ad] Endereço:Department of Biology & CESAM, University of Aveiro, 3810-193 Aveiro, Portugal. Electronic address: abarreto@ua.pt.
[Ti] Título:Genotoxicity of gemfibrozil in the gilthead seabream (Sparus aurata).
[So] Source:Mutat Res;821:36-42, 2017 Sep.
[Is] ISSN:1873-135X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Widespread use of pharmaceuticals and suboptimal wastewater treatment have led to increased levels of these substances in aquatic ecosystems. Lipid-lowering drugs such as gemfibrozil, which are among the most abundant human pharmaceuticals in the environment, may have deleterious effects on aquatic organisms. We examined the genotoxicity of gemfibrozil in a fish species, the gilthead seabream (Sparus aurata), which is commercially important in southern Europe. Following 96-h waterborne exposure, molecular (erythrocyte DNA strand breaks) and cytogenetic (micronuclei and other nuclear abnormalities in cells) endpoints were measured. Gemfibrozil was positive in both endpoints, at environmentally relevant concentrations, a result that raises concerns about the potential genotoxic effects of the drug in recipient waters.
[Mh] Termos MeSH primário: Quebras de DNA
Eritrócitos/efeitos dos fármacos
Genfibrozila/toxicidade
Micronúcleos com Defeito Cromossômico/induzido quimicamente
Dourada/genética
Poluentes Químicos da Água/toxicidade
[Mh] Termos MeSH secundário: Animais
Ensaio Cometa
Relação Dose-Resposta a Droga
Eritrócitos/patologia
Testes para Micronúcleos
Dourada/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Water Pollutants, Chemical); Q8X02027X3 (Gemfibrozil)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170821
[Lr] Data última revisão:
170821
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170725
[St] Status:MEDLINE


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[PMID]:28296193
[Au] Autor:Wang Q; Zheng M; Leil T
[Ad] Endereço:Quantitative Clinical Pharmacology, Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Princeton, New Jersey, USA.
[Ti] Título:Investigating Transporter-Mediated Drug-Drug Interactions Using a Physiologically Based Pharmacokinetic Model of Rosuvastatin.
[So] Source:CPT Pharmacometrics Syst Pharmacol;6(4):228-238, 2017 Apr.
[Is] ISSN:2163-8306
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Rosuvastatin is a frequently used probe in transporter-mediated drug-drug interaction (DDI) studies. This report describes the development of a physiologically based pharmacokinetic (PBPK) model of rosuvastatin for prediction of pharmacokinetic (PK) DDIs. The rosuvastatin model predicted the observed single (i.v. and oral) and multiple dose PK profiles, as well as the impact of coadministration with transporter inhibitors. The predicted effects of rifampin and cyclosporine (6.58-fold and 5.07-fold increase in rosuvastatin area under the curve (AUC), respectively) were mediated primarily via inhibition of hepatic organic anion-transporting polypeptide (OATP)1B1 (Inhibition constant (K ) ∼1.1 and 0.014 µM, respectively) and OATP1B3 (K ∼0.3 and 0.007 µM, respectively), with cyclosporine also inhibiting intestinal breast cancer resistance protein (BCRP; K ∼0.07 µM). The predicted effects of gemfibrozil and its metabolite were moderate (1.88-fold increase in rosuvastatin AUC) and mediated primarily via inhibition of hepatic OATP1B1 and renal organic cation transporter 3. This model of rosuvastatin will be useful in prospectively predicting transporter-mediated DDIs with novel pharmaceutical agents in development.
[Mh] Termos MeSH primário: Ciclosporina/administração & dosagem
Genfibrozila/administração & dosagem
Rifampina/administração & dosagem
Rosuvastatina Cálcica/administração & dosagem
[Mh] Termos MeSH secundário: Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo
Administração Intravenosa
Administração Oral
Área Sob a Curva
Ciclosporina/farmacocinética
Relação Dose-Resposta a Droga
Interações Medicamentosas
Genfibrozila/farmacocinética
Regulação da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Modelos Teóricos
Proteínas de Neoplasias/metabolismo
Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo
Rifampina/farmacocinética
Rosuvastatina Cálcica/farmacocinética
Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto
Membro 1b1 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCG2 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 2); 0 (Neoplasm Proteins); 0 (Organic Anion Transporters, Sodium-Independent); 0 (SLCO1B1 protein, human); 0 (SLCO1B3 protein, human); 0 (Solute Carrier Organic Anion Transporter Family Member 1B3); 0 (Solute Carrier Organic Anion Transporter Family Member 1b1); 83HN0GTJ6D (Cyclosporine); 83MVU38M7Q (Rosuvastatin Calcium); Q8X02027X3 (Gemfibrozil); VJT6J7R4TR (Rifampin)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170316
[St] Status:MEDLINE
[do] DOI:10.1002/psp4.12168


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[PMID]:28199020
[Au] Autor:Ghosh A; Rangasamy SB; Modi KK; Pahan K
[Ad] Endereço:Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
[Ti] Título:Gemfibrozil, food and drug administration-approved lipid-lowering drug, increases longevity in mouse model of late infantile neuronal ceroid lipofuscinosis.
[So] Source:J Neurochem;141(3):423-435, 2017 May.
[Is] ISSN:1471-4159
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL) is a rare neurodegenerative disease caused by mutations in the Cln2 gene that leads to deficiency or loss of function of the tripeptidyl peptidase 1 (TPP1) enzyme. TPP1 deficiency is known to cause the accumulation of autofluoroscent lipid-protein pigments in brain. Similar to other neurodegenerative disorders, LINCL is also associated with neuroinflammation and neuronal damage. Despite investigations, no effective therapy is currently available for LINCL. Therefore, we administered gemfibrozil (gem), an food and drug administration (FDA)-approved lipid-lowering drug, which has been shown to stimulate lysosomal biogenesis and induce anti-inflammation, orally, at a dose of 7.5 mg/kg body wt/day to Cln2 mice. We observed that gem-fed Cln2 mice lived longer by more than 10 weeks and had better motor activity compared to vehicle (0.1% Methyl cellulose) treatment. Gem treatment lowered the burden of storage materials, increased anti-inflammatory factors like SOCS3 and IL-1Ra, up-regulated anti-apoptotic molecule like phospho-Bad, and reduced neuronal apoptosis in the brain of Cln2 mice. Collectively, this study reinforces a neuroprotective role of gem that may be of therapeutic interest in improving the quality of life in LINCL patients.
[Mh] Termos MeSH primário: Genfibrozila/farmacologia
Genfibrozila/uso terapêutico
Hipolipemiantes/farmacologia
Hipolipemiantes/uso terapêutico
Longevidade/efeitos dos fármacos
Lipofuscinoses Ceroides Neuronais/tratamento farmacológico
[Mh] Termos MeSH secundário: Aminopeptidases/genética
Aminopeptidases/metabolismo
Animais
Apoptose/efeitos dos fármacos
Dipeptidil Peptidases e Tripeptidil Peptidases/genética
Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo
Proteína Antagonista do Receptor de Interleucina 1/metabolismo
Lisossomos/efeitos dos fármacos
Lisossomos/metabolismo
Camundongos
Camundongos Knockout
Atividade Motora/efeitos dos fármacos
Lipofuscinoses Ceroides Neuronais/patologia
Serina Proteases/genética
Serina Proteases/metabolismo
Proteína 3 Supressora da Sinalização de Citocinas/metabolismo
Proteína de Morte Celular Associada a bcl/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bad protein, mouse); 0 (Hypolipidemic Agents); 0 (Il1rn protein, mouse); 0 (Interleukin 1 Receptor Antagonist Protein); 0 (Socs3 protein, mouse); 0 (Suppressor of Cytokine Signaling 3 Protein); 0 (bcl-Associated Death Protein); EC 3.4.- (Serine Proteases); EC 3.4.11.- (Aminopeptidases); EC 3.4.14.- (Dipeptidyl-Peptidases and Tripeptidyl-Peptidases); EC 3.4.14.9 (tripeptidyl-peptidase 1); Q8X02027X3 (Gemfibrozil)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170502
[Lr] Data última revisão:
170502
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170216
[St] Status:MEDLINE
[do] DOI:10.1111/jnc.13987


  4 / 1299 MEDLINE  
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[PMID]:27987461
[Au] Autor:Fabbri D; Maurino V; Minella M; Minero C; Vione D
[Ad] Endereço:Università degli Studi di Torino, Dipartimento di Chimica, Via P. Giuria 5, 10125 Torino, Italy.
[Ti] Título:Modelling the photochemical attenuation pathways of the fibrate drug gemfibrozil in surface waters.
[So] Source:Chemosphere;170:124-133, 2017 Mar.
[Is] ISSN:1879-1298
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Gemfibrozil (GFZ) is a relatively persistent pollutant in surface-water environments and it is rather recalcitrant to biological degradation. The GFZ photochemical lifetimes are relatively short in shallow waters with low levels of dissolved organic carbon (DOC), but they can reach the month-year range in deep and high-DOC waters. The main reason is that GFZ undergoes negligible reaction with singlet oxygen or degradation sensitised by the triplet states of chromophoric dissolved organic matter, which are the usually prevalent photochemical pathways in deep and high-DOC sunlit waters. Nitrate and nitrite scarcely affect the overall GFZ lifetimes, but they can shift photodegradation from direct photolysis to the OH process. These two pathways are the main GFZ phototransformation routes, with the direct photolysis prevailing in shallow environments during summer. Under these conditions the GFZ photochemical lifetimes are also shorter and the environmental significance of photodegradation correspondingly higher. The direct photolysis of GFZ under UVB irradiation yielded several transformation intermediates deriving from oxidation or cleavage of the aliphatic lateral chain. A quinone derivative (2,5-dimethyl-1,4-benzoquinone), a likely oxidation product of the transformation intermediate 2,5-dimethylphenol, is expected to be the most acutely and chronically toxic compound arising from GFZ direct photolysis. Interestingly, literature evidence suggests that the same toxic intermediate would be formed upon OH reaction.
[Mh] Termos MeSH primário: Benzoquinonas/análise
Cicloexenos/análise
Genfibrozila/análise
Poluentes Químicos da Água/análise
[Mh] Termos MeSH secundário: Meio Ambiente
Meia-Vida
Radical Hidroxila/química
Cinética
Modelos Químicos
Modelos Teóricos
Nitratos/análise
Nitritos/análise
Oxigênio/química
Processos Fotoquímicos
Fotólise
Raios Ultravioleta
Água
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzoquinones); 0 (Cyclohexenes); 0 (Nitrates); 0 (Nitrites); 0 (Water Pollutants, Chemical); 059QF0KO0R (Water); 137-18-8 (2,5-dimethyl-4-benzoquinone); 3352-57-6 (Hydroxyl Radical); Q8X02027X3 (Gemfibrozil); S88TT14065 (Oxygen)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161218
[St] Status:MEDLINE


  5 / 1299 MEDLINE  
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[PMID]:27918198
[Au] Autor:Song D; Luo M; Dai M; Bu S; Wang W; Zhang B; Gonzalez FJ; Liu A
[Ad] Endereço:a Medical School of Ningbo University, Ningbo 315211, China.
[Ti] Título:PPARα-dependent increase of mouse urine output by gemfibrozil and fenofibrate.
[So] Source:Can J Physiol Pharmacol;95(2):199-205, 2017 Feb.
[Is] ISSN:1205-7541
[Cp] País de publicação:Canada
[La] Idioma:eng
[Ab] Resumo:While gemfibrozil and fenofibrate are prescribed for anti-dyslipidemia treatment, a rational basis for the use of these drugs for treatment of dyslipidemia with concurrent metabolic syndrome has not been established. In this study, wild-type and Pparα-null mice were fed gemfibrozil- or fenofibrate-containing diets for 14 days. Urine output (24 h) was monitored, and urine, serum, and liver and kidney tissues were subjected to toxicity assessment. A 2-month challenge followed by a 2-week wash-out was performed for gemfibrozil to determine urine output and the potential toxicity. A therapeutically equivalent dose of gemfibrozil was more effective than fenofibrate in increasing urine output. This regulatory effect was not observed in Pparα-null mice. In contrast, hepatomegaly induced by fenofibrate was more pronounced than that of gemfibrozil. No significant toxicity was observed in liver or kidney in the 2-month treatment with gemfibrozil. These data demonstrated PPARα mediates the increased urine output by fibrates. Considering the relative action on hepatomegaly and the regulatory effect on urine output, gemfibrozil may be the preferable drug to increase urine output. These results revealed a new pharmacodynamic effect of clinically prescribed PPARα agonists and suggested the potential value of gemfibrozil in modification of blood pressure.
[Mh] Termos MeSH primário: Diuréticos/farmacologia
Fenofibrato/farmacologia
Genfibrozila/farmacologia
Rim/efeitos dos fármacos
Fígado/efeitos dos fármacos
PPAR alfa/metabolismo
[Mh] Termos MeSH secundário: Alanina Transaminase/sangue
Aldosterona/sangue
Animais
Arginina Vasopressina/sangue
Aspartato Aminotransferases/sangue
Nitrogênio da Ureia Sanguínea
Creatinina/sangue
Fenofibrato/efeitos adversos
Genfibrozila/efeitos adversos
Hepatomegalia/induzido quimicamente
Homeostase
Rim/patologia
Fígado/patologia
Masculino
Camundongos
Camundongos Knockout
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Diuretics); 0 (PPAR alpha); 113-79-1 (Arginine Vasopressin); 4964P6T9RB (Aldosterone); AYI8EX34EU (Creatinine); EC 2.6.1.1 (Aspartate Aminotransferases); EC 2.6.1.2 (Alanine Transaminase); Q8X02027X3 (Gemfibrozil); U202363UOS (Fenofibrate)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170503
[Lr] Data última revisão:
170503
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161206
[St] Status:MEDLINE
[do] DOI:10.1139/cjpp-2016-0140


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[PMID]:27835067
[Au] Autor:Salesa B; Ferrando MD; Villarroel MJ; Sancho E
[Ad] Endereço:a Laboratory of Ecotoxicology, Department of Cellular Biology , Functional Biology and Physical Anthropology, Faculty of Biology, University of Valencia , Valencia , Spain.
[Ti] Título:Effect of the lipid regulator Gemfibrozil in the Cladocera Daphnia magna at different temperatures.
[So] Source:J Environ Sci Health A Tox Hazard Subst Environ Eng;52(3):228-234, 2017 Feb 23.
[Is] ISSN:1532-4117
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In the present study, an ecotoxicological approach to the evaluation of Gemfibrozil (GEM) as an emerging organic pollutant was done. In order to assess its toxicity, tests were conducted using the cladocera Daphnia magna. Experiments were carried out at 22°C and 28°C. EC , feeding behavior, and chronic toxicity tests (21 days) were evaluated in D. magna exposed to GEM as well as cholesterol levels at 21-day chronic exposure. D. magna GEM EC values (24 h) in our experimental conditions were 148.75 and 116.24 mg L at 22°C and 28°C, respectively. Test concentrations of 0.1, 0.5, 1.0, 5.0 and 7.5 mg L were selected for subacute and chronic experiments. Subacute short-term test (feeding study) was assessed after exposure to the toxicant. Filtration and ingestion rates of D. magna exposed animals did not show any significant difference (P > 0.05) with respect to control daphniids neither at 22°C nor at 28°C. Therefore, GEM test concentrations used in the present study did not reduce feeding behavior in D. magna. Temperature increased from 22°C to 28°C, which resulted in a decrease of the daphniids reproductive parameters such as brood size and number of young per female. Other parameters as longevity were not affected. The GEM concentrations used in the chronic test with D. magna did not affect daphniids longevity but some reproductive parameters as number of young per female or brood size were affected. Finally, a significant decreased in cholesterol levels was found in those animals exposed to the highest toxicant concentrations. More studies must be done to determine the possible implications of GEM in aquatic fauna and to derive its possible effects on the environment.
[Mh] Termos MeSH primário: Daphnia/efeitos dos fármacos
Genfibrozila/toxicidade
Hipolipemiantes/toxicidade
Poluentes Químicos da Água/toxicidade
[Mh] Termos MeSH secundário: Animais
Comportamento Alimentar/efeitos dos fármacos
Feminino
Dose Letal Mediana
Reprodução/efeitos dos fármacos
Temperatura Ambiente
Testes de Toxicidade Crônica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hypolipidemic Agents); 0 (Water Pollutants, Chemical); Q8X02027X3 (Gemfibrozil)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161112
[St] Status:MEDLINE
[do] DOI:10.1080/10934529.2016.1246937


  7 / 1299 MEDLINE  
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[PMID]:27648490
[Au] Autor:Varma MV; Kimoto E; Scialis R; Bi Y; Lin J; Eng H; Kalgutkar AS; El-Kattan AF; Rodrigues AD; Tremaine LM
[Ad] Endereço:Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut, USA.
[Ti] Título:Transporter-Mediated Hepatic Uptake Plays an Important Role in the Pharmacokinetics and Drug-Drug Interactions of Montelukast.
[So] Source:Clin Pharmacol Ther;101(3):406-415, 2017 Mar.
[Is] ISSN:1532-6535
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Montelukast, a leukotriene receptor antagonist commonly prescribed for treatment of asthma, is primarily metabolized by cytochrome P450 (CYP)2C8, and has been suggested as a probe substrate for investigating CYP2C8 activity in vivo. We evaluated the quantitative role of hepatic uptake transport in its pharmacokinetics and drug-drug interactions (DDIs). Montelukast was characterized with significant active uptake in human hepatocytes, and showed affinity towards organic anion transporting polypeptides (OATPs) in transfected cell systems. Single-dose rifampicin, an OATP inhibitor, decreased montelukast clearance in rats and monkeys. Clinical DDIs of montelukast were evaluated using physiologically based pharmacokinetic modeling; and simulation of the interactions with gemfibrozil-CYP2C8 and OATP1B1/1B3 inhibitor, clarithromycin-CYP3A and OATP1B1/1B3 inhibitor, and itraconazole-CYP3A inhibitor, implicated OATPs-CYP2C8-CYP2C8 interplay as the primary determinant of montelukast pharmacokinetics. In conclusion, hepatic uptake plays a key role in the pharmacokinetics of montelukast, which should be taken into account when interpreting clinical interactions.
[Mh] Termos MeSH primário: Acetatos/farmacologia
Citocromo P-450 CYP2C8/efeitos dos fármacos
Citocromo P-450 CYP2C8/metabolismo
Fígado/metabolismo
Transportadores de Ânions Orgânicos/antagonistas & inibidores
Quinolinas/farmacologia
[Mh] Termos MeSH secundário: Acetatos/farmacocinética
Animais
Claritromicina/farmacocinética
Inibidores do Citocromo P-450 CYP3A/metabolismo
Relação Dose-Resposta a Droga
Genfibrozila/farmacologia
Haplorrinos
Hepatócitos/metabolismo
Modelos Biológicos
Inibidores da Síntese de Ácido Nucleico
Transportadores de Ânions Orgânicos/metabolismo
Quinolinas/farmacocinética
Ratos
Rifampina/farmacologia
Membro 1b1 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetates); 0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Nucleic Acid Synthesis Inhibitors); 0 (Organic Anion Transporters); 0 (Quinolines); 0 (Solute Carrier Organic Anion Transporter Family Member 1b1); EC 1.14.14.1 (Cytochrome P-450 CYP2C8); H1250JIK0A (Clarithromycin); MHM278SD3E (montelukast); Q8X02027X3 (Gemfibrozil); VJT6J7R4TR (Rifampin)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170517
[Lr] Data última revisão:
170517
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160921
[St] Status:MEDLINE
[do] DOI:10.1002/cpt.520


  8 / 1299 MEDLINE  
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[PMID]:27548563
[Au] Autor:Tornio A; Neuvonen PJ; Niemi M; Backman JT
[Ad] Endereço:a Department of Clinical Pharmacology , University of Helsinki and Helsinki University Hospital , Helsinki , Finland.
[Ti] Título:Role of gemfibrozil as an inhibitor of CYP2C8 and membrane transporters.
[So] Source:Expert Opin Drug Metab Toxicol;13(1):83-95, 2017 Jan.
[Is] ISSN:1744-7607
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Cytochrome P450 (CYP) 2C8 is a drug metabolizing enzyme of major importance. The lipid-lowering drug gemfibrozil has been identified as a strong inhibitor of CYP2C8 in vivo. This effect is due to mechanism-based inhibition of CYP2C8 by gemfibrozil 1-O-ß-glucuronide. In vivo, gemfibrozil is a fairly selective CYP2C8 inhibitor, which lacks significant inhibitory effect on other CYP enzymes. Gemfibrozil can, however, have a smaller but clinically meaningful inhibitory effect on membrane transporters, such as organic anion transporting polypeptide 1B1 and organic anion transporter 3. Areas covered: This review describes the inhibitory effects of gemfibrozil on CYP enzymes and membrane transporters. The clinical drug interactions caused by gemfibrozil and the different mechanisms contributing to the interactions are reviewed in detail. Expert opinion: Gemfibrozil is a useful probe inhibitor of CYP2C8 in vivo, but its effect on membrane transporters has to be taken into account in study design and interpretation. Moreover, gemfibrozil could be used to boost the pharmacokinetics of CYP2C8 substrate drugs. Identification of gemfibrozil 1-O-ß-glucuronide as a potent mechanism-based inhibitor of CYP2C8 has led to recognition of glucuronide metabolites as perpetrators of drug-drug interactions. Recently, also acyl glucuronide metabolites of clopidogrel and deleobuvir have been shown to strongly inhibit CYP2C8.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP2C8/farmacologia
Genfibrozila/farmacologia
Proteínas de Membrana Transportadoras/efeitos dos fármacos
[Mh] Termos MeSH secundário: Citocromo P-450 CYP2C8/efeitos dos fármacos
Inibidores do Citocromo P-450 CYP2C8/metabolismo
Interações Medicamentosas
Genfibrozila/análogos & derivados
Genfibrozila/metabolismo
Glucuronatos/metabolismo
Glucuronatos/farmacologia
Seres Humanos
Hipolipemiantes/metabolismo
Hipolipemiantes/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2C8 Inhibitors); 0 (Glucuronates); 0 (Hypolipidemic Agents); 0 (Membrane Transport Proteins); 91683-38-4 (gemfibrozil 1-O-acylglucuronide); EC 1.14.14.1 (CYP2C8 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2C8); Q8X02027X3 (Gemfibrozil)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170210
[Lr] Data última revisão:
170210
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160823
[St] Status:MEDLINE


  9 / 1299 MEDLINE  
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[PMID]:28057168
[Au] Autor:Patel NJ; Wickremsinhe E; Hui YH; Barr A; Masterson N; Ruterbories K; Weller J; Hanes J; Kern T; Perkins E
[Ad] Endereço:Drug Disposition Eli Lilly and Company, Indianapolis, USA.
[Ti] Título:Evaluation and Optimization of Blood Micro-Sampling Methods: Serial Sampling in a Cross-Over Design from an Individual Mouse.
[So] Source:J Pharm Pharm Sci;19(4):496-510, 2016 Oct - Dec.
[Is] ISSN:1482-1826
[Cp] País de publicação:Canada
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Current practices applied to mouse pharmacokinetic (PK) studies often use large numbers of animals with sporadic or composite sampling that inadequately describe PK profiles.  The purpose of this work was to evaluate and optimize blood microsampling techniques coupled with dried blood spot (DBS) and LC-MS/MS analysis to generate reliable PK data in mice.  In addition, the feasibility of cross-over designs was assessed and recommendations are presented. METHODS: The work describes a comprehensive evaluation of five blood microsampling techniques (tail clip, tail vein with needle hub, submandibular, retro-orbital, and saphenous bleeding) in CD-1 mice.  The feasibility of blood sampling was evaluated based on animal observations, ease of bleeding, and ability to collect serial samples.  Methotrexate, gemfibrozil and glipizide were used as test compounds and were dosed either orally or intravenously, followed by DBS collection and LC-MS/MS analysis to compare PK with various bleeding methods. RESULTS: Submandibular and retro-orbital methods that required non-serial blood collections did not allow for inter-animal variability assessments and resulted in poorly described absorption and distribution kinetics.  The submandibular and tail vein with needle-hub methods were the least favorable from a technical feasibility perspective.  Serial bleeding was possible with cannulated animals or saphenous bleeding in non-cannulated animals. CONCLUSIONS:   Of the methods that allowed serial sampling, the saphenous method when executed as described in this report, was most practical, reproducible and provided for assessment of inter-animal variability.  It enabled the collection of complete exposure profiles from a single mouse and the conduct of an intravenous/oral cross-over study design.  This methodology can be used routinely, it promotes the 3Rs principles by achieving reductions in the number of animals used, decreased restraints and animal stress, and improved the quality of data obtained in mouse PK studies. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
[Mh] Termos MeSH primário: Coleta de Amostras Sanguíneas
Teste em Amostras de Sangue Seco
Genfibrozila/sangue
Glipizida/sangue
Metotrexato/sangue
[Mh] Termos MeSH secundário: Animais
Cromatografia Líquida
Estudos Cross-Over
Masculino
Camundongos
Espectrometria de Massas em Tandem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
Q8X02027X3 (Gemfibrozil); X7WDT95N5C (Glipizide); YL5FZ2Y5U1 (Methotrexate)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170107
[St] Status:MEDLINE
[do] DOI:10.18433/J3NK60


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[PMID]:27849333
[Au] Autor:Jakob T; Nordmann AJ; Schandelmaier S; Ferreira-González I; Briel M
[Ad] Endereço:Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Basel, Switzerland.
[Ti] Título:Fibrates for primary prevention of cardiovascular disease events.
[So] Source:Cochrane Database Syst Rev;11:CD009753, 2016 11 16.
[Is] ISSN:1469-493X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Fibrates are effective for modifying atherogenic dyslipidaemia, and particularly for lowering serum triglycerides. However, evidence that fibrates reduce mortality and morbidity associated with cardiovascular disease (CVD), or overall mortality and morbidity, in the primary prevention of CVD is lacking. OBJECTIVES: This Cochrane Review and meta-analysis aimed to evaluate the clinical benefits and harms of fibrates versus placebo or usual care or fibrates plus other lipid-modifying drugs versus other lipid-modifying drugs alone for the primary prevention of cardiovascular disease (CVD) morbidity and mortality. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCO), and Web of Science (all from inception to 19 May 2016). We searched four clinical trial registers (last searched on 3 August 2016) with the help of an experienced professional librarian. We searched the databases to identify randomised controlled trials (RCTs) evaluating the clinical effects of fibrate therapy in the primary prevention of CVD events. We did not impose any language restrictions. SELECTION CRITERIA: We aimed to include all RCTs comparing the effects of fibrate monotherapy versus placebo or usual care, or fibrates plus other lipid-modifying drugs versus other lipid-modifying drugs alone. Included studies had a follow-up of at least six months for the primary prevention of CVD events. We excluded trials with clofibrate, because it was withdrawn from the market in 2002. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts for potential study inclusion. Two review authors independently retrieved the full-text papers and extracted data. Disagreements were resolved by consensus. We calculated risk ratios (RRs) and accompanying 95% confidence intervals (CIs) for aggregate data on primary and secondary outcomes. We tested for heterogeneity with the Cochrane Q-test and used the I statistic to measure inconsistency of treatment effects across studies. Using the GRADE approach, we assessed the quality of the evidence and used the GRADE profiler software (GRADEpro GDT) to import data from Review Manager 5 to create 'Summary of findings' tables. MAIN RESULTS: We identified six eligible trials including 16,135 individuals. The mean age of trial populations varied across trials; between 47.3 and 62.3 years. Four trials included individuals with diabetes mellitus type 2 only. The mean treatment duration and follow-up of participants across trials was 4.8 years. We judged the risks of selection and performance bias to be low; risks of detection bias, attrition bias, and reporting bias were unclear. Reporting of adverse effects by included trials was very limited; that is why we used discontinuation of therapy due to adverse effects as a proxy for adverse effects. Patients treated with fibrates had a reduced risk for the combined primary outcome of CVD death, non-fatal myocardial infarction, or non-fatal stroke compared to patients on placebo (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.74 to 0.96; participants = 16,135; studies = 6; moderate-quality of evidence). For secondary outcomes we found RRs for fibrate therapy compared with placebo of 0.79 for combined coronary heart disease death or non-fatal myocardial infarction (95% CI 0.68 to 0.92; participants = 16,135; studies = 6; moderate-quality of evidence); 1.01 for overall mortality (95% CI 0.81 to 1.26; participants = 8471; studies = 5; low-quality of evidence); 1.01 for non-CVD mortality (95% CI 0.76 to 1.35; participants = 8471; studies = 5; low-quality of evidence); and 1.38 for discontinuation of therapy due to adverse effects (95% CI 0.71 to 2.68; participants = 4805; studies = 3; I = 74%; very low-quality of evidence). Data on quality of life were not available from any trial. Trials that evaluated fibrates in the background of statins (2 studies) showed no benefits in preventing cardiovascular events. AUTHORS' CONCLUSIONS: Moderate-quality evidence suggests that fibrates lower the risk for cardiovascular and coronary events in primary prevention, but the absolute treatment effects in the primary prevention setting are modest (absolute risk reductions < 1%). There is low-quality evidence that fibrates have no effect on overall or non-CVD mortality. Very low-quality evidence suggests that fibrates are not associated with increased risk for adverse effects.
[Mh] Termos MeSH primário: Doenças Cardiovasculares/prevenção & controle
Hipolipemiantes/uso terapêutico
Prevenção Primária
[Mh] Termos MeSH secundário: Atorvastatina Cálcica/uso terapêutico
Bezafibrato/uso terapêutico
Doenças Cardiovasculares/mortalidade
Ácido Clofíbrico/análogos & derivados
Ácido Clofíbrico/uso terapêutico
Fenofibrato/uso terapêutico
Genfibrozila/uso terapêutico
Seres Humanos
Hipolipemiantes/efeitos adversos
Meia-Idade
Infarto do Miocárdio/epidemiologia
Infarto do Miocárdio/mortalidade
Prevenção Primária/normas
Sinvastatina/uso terapêutico
Acidente Vascular Cerebral/epidemiologia
Acidente Vascular Cerebral/mortalidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Hypolipidemic Agents); 23TF67G79M (etofibrate); 48A5M73Z4Q (Atorvastatin Calcium); 53PF01Q249 (Clofibric Acid); AGG2FN16EV (Simvastatin); Q8X02027X3 (Gemfibrozil); U202363UOS (Fenofibrate); Y9449Q51XH (Bezafibrate)
[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:161117
[St] Status:MEDLINE



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