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[PMID]:27777271
[Au] Autor:Lee HH; Leake BF; Kim RB; Ho RH
[Ad] Endereço:Division of Hematology and Oncology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee (H.H.L., B.F.L., R.H.H.); and Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Can
[Ti] Título:Contribution of Organic Anion-Transporting Polypeptides 1A/1B to Doxorubicin Uptake and Clearance.
[So] Source:Mol Pharmacol;91(1):14-24, 2017 Jan.
[Is] ISSN:1521-0111
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The organic anion-transporting polypeptides represent an important family of drug uptake transporters that mediate the cellular uptake of a broad range of substrates including numerous drugs. Doxorubicin is a highly efficacious and well-established anthracycline chemotherapeutic agent commonly used in the treatment of a wide range of cancers. Although doxorubicin is a known substrate for efflux transporters such as P-glycoprotein (P-gp; MDR1, ABCB1), significantly less is known regarding its interactions with drug uptake transporters. Here, we investigated the role of organic anion transporting polypeptide (OATP) transporters to the disposition of doxorubicin. A recombinant vaccinia-based method for expressing uptake transporters in HeLa cells revealed that OATP1A2, but not OATP1B1 or OATP1B3, and the rat ortholog Oatp1a4 were capable of significant doxorubicin uptake. Interestingly, transwell assays using Madin-Darby canine kidney II cell line cells stably expressing specific uptake and/or efflux transporters revealed that OATP1B1, OATP1B3, and OATP1A2, either alone or in combination with MDR1, significantly transported doxorubicin. An assessment of polymorphisms in SLCO1A2 revealed that four variants were associated with significantly impaired doxorubicin transport in vitro. In vivo doxorubicin disposition studies revealed that doxorubicin plasma area under the curve was significantly higher (1.7-fold) in Slco1a/1b versus wild-type mice. The liver-to-plasma ratio of doxorubicin was significantly decreased (2.3-fold) in Slco1a/1b2 mice and clearance was reduced by 40% compared with wild-type mice, suggesting Oatp1b transporters are important for doxorubicin hepatic uptake. In conclusion, we demonstrate important roles for OATP1A/1B in transporter-mediated uptake and disposition of doxorubicin.
[Mh] Termos MeSH primário: Doxorrubicina/metabolismo
Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo
Transportadores de Ânions Orgânicos/metabolismo
Proteínas de Transporte de Cátions Orgânicos/metabolismo
[Mh] Termos MeSH secundário: Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo
Animais
Transporte Biológico
Membrana Celular/metabolismo
Cães
Células HeLa
Seres Humanos
Cinética
Fígado/metabolismo
Células Madin Darby de Rim Canino
Masculino
Camundongos
Modelos Biológicos
Proteínas Mutantes/metabolismo
Ratos
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATP-Binding Cassette, Sub-Family B, Member 1); 0 (Mutant Proteins); 0 (Oatp1a1 protein, mouse); 0 (Organic Anion Transporters); 0 (Organic Anion Transporters, Sodium-Independent); 0 (Organic Cation Transport Proteins); 0 (SLCO1A2 protein, human); 0 (Slco1b2 protein, mouse); 80168379AG (Doxorubicin)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:180101
[Lr] Data última revisão:
180101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE


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[PMID]:28890383
[Au] Autor:Yuan Y; Yang H; Kong L; Li Y; Li P; Zhang H; Ruan J
[Ad] Endereço:College of Pharmaceutical Sciences, Soochow University, Suzhou, China; Department of Pharmacy, Wuxi Maternity and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi, China.
[Ti] Título:Interaction between rhein acyl glucuronide and methotrexate based on human organic anion transporters.
[So] Source:Chem Biol Interact;277:79-84, 2017 Nov 01.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Rhein, a major bioactive compound of many medicinal herbs and the prodrug of diacerein, is often used with low dose of methotrexate as drug combination to treat rheumatoid arthritis. In this study, potential drug-drug interaction between methotrexate and rhein was investigated based on organic anion transporters (OAT). Our study demonstrated that rhein acyl glucuronide (RAG), the major metabolite of rhein in the human blood circulation, significantly inhibited the uptake of p-aminohippurate in hOAT1 transfected cells with IC value of 691 nM and estrone sulfate uptake in hOAT3 transfected cells with IC value of 78.5 nM. As the substrate of both hOAT1 and hOAT3, the methotrexate transport was significantly inhibited by RAG in hOAT1 transfected cells at 50 µM and hOAT3 transfected cells at 1 µM by 69% and 87%, respectively. Further in vivo study showed that after co-administrated with RAG in rats the AUC values of methotrexate increased from 3109 to 5370 ng/mL*hr and the t was prolonged by 40.5% (from 7.4 to 10.4 h), demonstrating the inhibitory effect of RAG on methotrexate excretion. In conclusion, rhein acyl glucuronide could significantly decrease the transport of methotrexate by both hOAT1 and hOAT3. The combination use of rhein, diacerein or other rhein-containing herbs with methotrexate may cause obvious drug-drug interaction and require close monitoring for potential drug interaction in clinical practice.
[Mh] Termos MeSH primário: Antraquinonas/farmacologia
Antirreumáticos/farmacocinética
Inibidores Enzimáticos/farmacologia
Glucuronídeos/farmacologia
Metotrexato/farmacocinética
Transportadores de Ânions Orgânicos/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Antraquinonas/metabolismo
Interações Medicamentosas
Inibidores Enzimáticos/metabolismo
Glucuronídeos/metabolismo
Células HEK293
Seres Humanos
Masculino
Proteína 1 Transportadora de Ânions Orgânicos/antagonistas & inibidores
Proteína 1 Transportadora de Ânions Orgânicos/metabolismo
Transportadores de Ânions Orgânicos/metabolismo
Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores
Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anthraquinones); 0 (Antirheumatic Agents); 0 (Enzyme Inhibitors); 0 (Glucuronides); 0 (Organic Anion Transport Protein 1); 0 (Organic Anion Transporters); 0 (Organic Anion Transporters, Sodium-Independent); 0 (SLC22A7 protein, human); YL5FZ2Y5U1 (Methotrexate); YM64C2P6UX (rhein)
[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:170912
[St] Status:MEDLINE


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[PMID]:28765282
[Au] Autor:Bush KT; Wu W; Lun C; Nigam SK
[Ad] Endereço:From the Departments of Pediatrics.
[Ti] Título:The drug transporter OAT3 (SLC22A8) and endogenous metabolite communication via the gut-liver-kidney axis.
[So] Source:J Biol Chem;292(38):15789-15803, 2017 Sep 22.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The organic anion transporters OAT1 (SLC22A6) and OAT3 (SLC22A8) have similar substrate specificity for drugs, but it is far from clear whether this holds for endogenous substrates. By analysis of more than 600 metabolites in the (Oat3 knockout) by LC/MS, we demonstrate OAT3 involvement in the movement of gut microbiome products, key metabolites, and signaling molecules, including those flowing through the gut-liver-kidney axis. Major pathways affected included those involved in metabolism of bile acids, flavonoids, nutrients, amino acids (including tryptophan-derivatives that are uremic toxins), and lipids. OAT3 is also critical in elimination of liver-derived phase II metabolites, particularly those undergoing glucuronidation. Analysis of physicochemical features revealed nine distinct metabolite groups; at least one member of most clusters has been previously validated in transport assays. In contrast to drugs interacting with the OATs, endogenous metabolites accumulating in the (Oat1 knockout) have distinct differences in their physicochemical properties; they are very different in size, number of rings, hydrophobicity, and molecular complexity. Consistent with the Remote Sensing and Signaling Hypothesis, the data support the importance of the OAT transporters in inter-organ and inter-organismal remote communication via transporter-mediated movement of key metabolites and signaling molecules ( gut microbiome-to-intestine-to-blood-to-liver-to-kidney-to-urine). We discuss the possibility of an intimate connection between OATs and metabolite sensing and signaling pathways ( bile acids). Furthermore, the metabolomics and pathway analysis support the view that OAT1 plays a greater role in kidney proximal tubule metabolism and OAT3 appears relatively more important in systemic metabolism, modulating levels of metabolites flowing through intestine, liver, and kidney.
[Mh] Termos MeSH primário: Intestinos/metabolismo
Rim/metabolismo
Fígado/metabolismo
Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo
[Mh] Termos MeSH secundário: Aminoácidos/metabolismo
Animais
Ácidos e Sais Biliares/metabolismo
Dieta
Metabolismo Energético
Microbioma Gastrointestinal
Técnicas de Inativação de Genes
Intestinos/microbiologia
Ligantes
Metabolismo dos Lipídeos
Masculino
Metabolômica
Camundongos
Camundongos Endogâmicos C57BL
Proteína 1 Transportadora de Ânions Orgânicos/metabolismo
Transportadores de Ânions Orgânicos Sódio-Independentes/deficiência
Transportadores de Ânions Orgânicos Sódio-Independentes/genética
Especificidade por Substrato
Xenobióticos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids); 0 (Bile Acids and Salts); 0 (Ligands); 0 (Organic Anion Transport Protein 1); 0 (Organic Anion Transporters, Sodium-Independent); 0 (Slc22a6 protein, mouse); 0 (Xenobiotics); 0 (organic anion transport protein 3)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170803
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.796516


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[PMID]:28644885
[Au] Autor:Zhang Y; Boxberger KH; Hagenbuch B
[Ad] Endereço:Department of Pharmacology, Toxicology and Therapeutics, the University of Kansas Medical Center, Kansas City, Kansas, United States of America.
[Ti] Título:Organic anion transporting polypeptide 1B3 can form homo- and hetero-oligomers.
[So] Source:PLoS One;12(6):e0180257, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OATP1B3 is a 12 transmembrane domain protein expressed at the basolateral membrane of human hepatocytes where it mediates the uptake of numerous drugs and endogenous compounds. Previous western blot results suggest the formation of OATP1B3 multimers. In order to better understand the function of OATP1B3 under normal physiological conditions, we investigated its oligomerization status. We transiently transfected OATP1B3 with a C-terminal His-, FLAG- or HA-tag in HEK293 cells and used co-immunoprecipitation and a Proximity Ligation Assay to detect interactions between the different constructs. All three constructs retained similar transport rates as wild-type OATP1B3. Immunofluorescence experiments indicated that in contrast to wild-type, His- and FLAG-tagged OATP1B3, where the C-terminal end is on the cytoplasmic side of the membrane, the C-terminal end of HA-tagged OATP1B3 is extracellular. After cross-linking, anti-FLAG antibodies were able to pull down FLAG-tagged OATP1B3 (positive control) and co-transfected His- or HA-tagged OATP1B3, demonstrating the formation of homo-oligomers and suggesting that the C-terminal part is not involved in oligomer formation. We confirmed co-localization of His- and FLAG-tagged OATP1B3 in transfected HEK293 cells with the Proximity Ligation Assay. Transport studies with a non-functional OATP1B3 mutant suggest that the individual subunits and not the whole oligomer are the functional units in the homo-oligomers. In addition, we also detected OATP1B3-FLAG co-localization with OATP1B1-His or NTCP-His, suggesting that OATP1B3 also hetero-oligomerizes with other transport proteins. Using the Proximity Ligation Assay with transporter specific antibodies, we demonstrate close association of OATP1B3 with NTCP in frozen human liver tissue. These findings demonstrate that OATP1B3 can form homo- and hetero-oligomers and suggest a potential co-regulation of the involved transporters.
[Mh] Termos MeSH primário: Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo
[Mh] Termos MeSH secundário: Western Blotting
Citoplasma/metabolismo
Espaço Extracelular/metabolismo
Imunofluorescência
Células HEK293
Seres Humanos
Imunoprecipitação
Mutação
Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo
Transportadores de Ânions Orgânicos Sódio-Independentes/química
Transportadores de Ânions Orgânicos Sódio-Independentes/genética
Domínios Proteicos
Multimerização Proteica
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
Simportadores/metabolismo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Organic Anion Transporters, Sodium-Dependent); 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); 0 (Symporters); 145420-23-1 (sodium-bile acid cotransporter)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170624
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0180257


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[PMID]:28630284
[Au] Autor:Burckhardt BC; Henjakovic M; Hagos Y; Burckhardt G
[Ad] Endereço:Center of Physiology and Pathophysiology, University Medical Center Goettingen, Goettingen, Germany (B.C.B, M.H., Y.H., G.B.); Department I of Internal Medicine, University Medical Center Cologne, Cologne, Germany (M.H.); and PortaCellTec Biosciences GmbH, Goettingen, Germany (Y.H.) birgitta.burckha
[Ti] Título:Differential Interaction of Dantrolene, Glafenine, Nalidixic Acid, and Prazosin with Human Organic Anion Transporters 1 and 3.
[So] Source:J Pharmacol Exp Ther;362(3):450-458, 2017 Sep.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In renal proximal tubule cells, the organic anion transporters 1 and 3 (OAT1 and OAT3) in the basolateral membrane and the multidrug resistance-associated protein 4 (MRP4) in the apical membrane share substrates and co-operate in renal drug secretion. We hypothesized that recently identified MRP4 inhibitors dantrolene, glafenine, nalidixic acid, and prazosin also interact with human OAT1 and/or OAT3 stably transfected in human embryonic kidney 293 cells. These four drugs were tested as possible inhibitors of -[ H]aminohippurate (PAH) and [ C]glutarate uptake by OAT1, and of [ H]estrone-3-sulfate (ES) uptake by OAT3. In addition, we explored whether these drugs decrease the equilibrium distribution of radiolabeled PAH, glutarate, or ES, an approach intended to indirectly suggest drug/substrate exchange through OAT1 and OAT3. With OAT3, a dose-dependent inhibition of [ H]ES uptake and a downward shift in [ H]ES equilibrium were observed, indicating that all four drugs bind to OAT3 and may possibly be translocated. In contrast, the interaction with OAT1 was more complex. With [ C]glutarate as substrate, all four drugs inhibited uptake but only glafenine and nalidixic acid shifted glutarate equilibrium. Using [ H]PAH as a substrate of OAT1, nalidixic acid inhibited but dantrolene, glafenine, and prazosin stimulated uptake. Nalidixic acid decreased equilibrium content of [ H]PAH, suggesting that it may possibly be exchanged by OAT1. Taken together, OAT1 and OAT3 interact with the MRP4 inhibitors dantrolene, glafenine, nalidixic acid, and prazosin, indicating overlapping specificities. At OAT1, more than one binding site must be assumed to explain substrate and drug-dependent stimulation and inhibition of transport activity.
[Mh] Termos MeSH primário: Dantroleno/metabolismo
Glafenina/metabolismo
Ácido Nalidíxico/metabolismo
Proteína 1 Transportadora de Ânions Orgânicos/metabolismo
Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo
Prazosina/metabolismo
[Mh] Termos MeSH secundário: Ligação Competitiva
Técnicas de Cultura de Células
Estrona/análogos & derivados
Estrona/metabolismo
Células HEK293
Seres Humanos
Taxa de Depuração Metabólica
Proteína 1 Transportadora de Ânions Orgânicos/genética
Transportadores de Ânions Orgânicos Sódio-Independentes/genética
Ligação Proteica
Ensaio Radioligante
Eliminação Renal
Especificidade por Substrato
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Organic Anion Transport Protein 1); 0 (Organic Anion Transporters, Sodium-Independent); 0 (organic anion transport protein 3); 2DI9HA706A (Estrone); 3B91HWA56M (Nalidixic Acid); 46HL4I09AH (Glafenine); F64QU97QCR (Dantrolene); QTL48N278K (estrone sulfate); XM03YJ541D (Prazosin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.117.241406


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[PMID]:28559139
[Au] Autor:Kawasaki T; Takeichi Y; Tomita M; Uwai Y; Epifano F; Fiorito S; Taddeo VA; Genovese S; Nabekura T
[Ad] Endereço:Department of Pharmaceutics, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto, Chikusa-ku, Nagoya 464-8650, Japan.
[Ti] Título:Effects of phenylpropanoids on human organic anion transporters hOAT1 and hOAT3.
[So] Source:Biochem Biophys Res Commun;489(4):375-380, 2017 Aug 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human organic anion transporters hOAT1/SLC22A6 and hOAT3/SLC22A8 are highly expressed on the basolateral membrane of renal proximal tubules and mediate tubular uptake of anionic drugs from blood. They play an important role for drug disposition, and therefore close studies of their ligand recognition are important for drug therapy and development. In this study, we performed uptake experiments using HEK293 and fluorescent anion 6-carboxyfluorescein to asses the effects of phenylpropanoids on hOAT1 and hOAT3. We found that phenylpropanoids, 3-(4'-isopentenyloxyphenyl)-benzoic acid (IBA), 3-(4'-isopentenyloxy-3'-methoxyphenyl)-benzoic acid (IMBA), and 3-(4'-geranyloxy-3'-methoxy phenyl)-benzoic acid (GMBA) inhibited hOAT1 and hOAT3. The K values for hOAT1 were comparable to that of probenecid, a strong inhibitor of hOAT1 and hOAT3. While IBA demonstrated competitive inhibition, IMBA and GMBA showed mixed-type inhibition. After preincubation and washout, the inhibitory effects remained with IMBA and GMBA but not IBA, suggesting that the functional group at 3'-position is responsible for these differences. In conclusion, IBA, IMBA, and GMBA are inhibitors of hOAT1 and hOAT3.
[Mh] Termos MeSH primário: Proteína 1 Transportadora de Ânions Orgânicos/antagonistas & inibidores
Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores
Fenilpropionatos/farmacologia
[Mh] Termos MeSH secundário: Células Cultivadas
Relação Dose-Resposta a Droga
Células HEK293
Seres Humanos
Estrutura Molecular
Proteína 1 Transportadora de Ânions Orgânicos/metabolismo
Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo
Fenilpropionatos/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Organic Anion Transport Protein 1); 0 (Organic Anion Transporters, Sodium-Independent); 0 (Phenylpropionates); 0 (organic anion transport protein 3)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170601
[St] Status:MEDLINE


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[PMID]:28518053
[Au] Autor:Pei Q; Yang L; Tan HY; Liu SK; Liu Y; Huang L; Li RH; Wan Q; Huang J; Guo CX; Zuo XC; Li J; Yang GP
[Ti] Título:Effects of genetic variants in UGT1A1, SLCO1B3, ABCB1, ABCC2, ABCG2, ORM1 on PK/PD of telmisartan in Chinese patients with mild to moderate essential hypertension
.
[So] Source:Int J Clin Pharmacol Ther;55(8):659-665, 2017 Aug.
[Is] ISSN:0946-1965
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: This study aimed to understand the effects of single nucleotide polymorphisms (SNPs) in UGT1A1, SLCO1B3, ABCB1, ABCC2, ABCG2, and ORM1 on the pharmacokinetics (PK) (plasma concentration) and pharmacodynamics (PD) (blood pressure) of telmisartan in Chinese patients. METHODS: 58 Han Chinese patients (aged 45 - 72 years) with mild to moderate essential hypertension were included and received 80 mg/day telmisartan for 4 weeks. The plasma concentration and genetic variants were determined by LC/MS/MS and MALDI-TOF mass spectrometry, respectively. Multivariable linear analysis was used to examine the relationships between PK/PD and genetic variants. RESULTS: Females showed a significantly higher AUClast than males (n = 22, 4,879.48 ± 3,449.33 h×ng/mL vs. n = 36, 2,715.59 ± 2,223.77 h×ng/mL, p = 0.047). Amongst all genetic variants investigated, the patients with UGT1A1 rs4124874 AA (n = 11, 1,730.51 ± 1,325.79 h×ng/mL) had a significantly lower AUClast compared with patients with UGT1A1 rs4124874 CC+AC (n = 19 + 28, 4,177.44 ± 3,222.11 h×ng/mL and 3,810.82 ± 2,960.43 h×ng/mL, p = 0.027). None of the SNPs investigated was associated with the PD responses to telmisartan. CONCLUSION: Variation of UGT1A1 (rs4124874) affects PK of telmisartan in Chinese patients, highlighting the value of genetic testing in precision medicine as the telmisartan dose could be adjusted based on UGT1A1 genetic variations.
.
[Mh] Termos MeSH primário: Grupo com Ancestrais do Continente Asiático/genética
Benzimidazóis/farmacocinética
Benzimidazóis/uso terapêutico
Benzoatos/farmacocinética
Benzoatos/uso terapêutico
Hipertensão/tratamento farmacológico
Hipertensão/genética
Polimorfismo de Nucleotídeo Único/genética
[Mh] Termos MeSH secundário: Subfamília B de Transportador de Cassetes de Ligação de ATP/genética
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Idoso
Hipertensão Essencial
Feminino
Genótipo
Glucuronosiltransferase/genética
Seres Humanos
Masculino
Meia-Idade
Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética
Proteínas de Neoplasias/genética
Transportadores de Ânions Orgânicos Sódio-Independentes/genética
Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCB1 protein, human); 0 (ABCG2 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family B); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 2); 0 (Benzimidazoles); 0 (Benzoates); 0 (Multidrug Resistance-Associated Proteins); 0 (Neoplasm Proteins); 0 (Organic Anion Transporters, Sodium-Independent); 0 (SLCO1B3 protein, human); 0 (Solute Carrier Organic Anion Transporter Family Member 1B3); 4AF605U6JN (multidrug resistance-associated protein 2); EC 2.4.1.- (UGT1A1 enzyme); EC 2.4.1.17 (Glucuronosyltransferase); U5SYW473RQ (telmisartan)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170519
[St] Status:MEDLINE
[do] DOI:10.5414/CP202744


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[PMID]:28472795
[Au] Autor:Favretto G; Souza LM; Gregório PC; Cunha RS; Maciel RAP; Sassaki GL; Toledo MG; Pecoits-Filho R; Souza WM; Stinghen AEM
[Ad] Endereço:Experimental Nephrology Laboratory, Basic Pathology Department, Universidade Federal do Paraná, Curitiba, Brazil.
[Ti] Título:Role of Organic Anion Transporters in the Uptake of Protein-Bound Uremic Toxins by Human Endothelial Cells and Monocyte Chemoattractant Protein-1 Expression.
[So] Source:J Vasc Res;54(3):170-179, 2017.
[Is] ISSN:1423-0135
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Organic anion transporters (OATs) are involved in the uptake of uremic toxins such as p-cresyl sulfate (PCS) and indoxyl sulfate (IS), which play a role in endothelial dysfunction in patients with chronic kidney diseases (CKD). In this study, we investigated the role of OAT1 and OAT3 in the uptake of PCS and IS into human endothelial cells. PCS was synthesized via p-cresol sulfation and characterized using analytical methods. The cells were treated with PCS and IS in the absence and presence of probenecid (Pb), an OAT inhibitor. Cell viability was assessed using the MTT assay. The absorbed toxins were analyzed using chromatography, OAT expression using immunocytochemistry and western blot, and monocyte chemoattractant protein-1 (MCP-1) expression using enzyme-linked immunosorbent assay. Cell viability decreased after toxin treatment in a dose-dependent manner. PCS and IS showed significant internalization after 60 min treatment, while no internalization was observed in the presence of Pb, suggesting that OATs are involved in the transport of both toxins. Immunocytochemistry and western blot demonstrated OAT1 and OAT3 expression in endothelial cells. MCP-1 expression increased after toxins treatment but decreased after Pb treatment. PCS and IS uptake were mediated by OATs, and OAT blockage could serve as a therapeutic strategy to inhibit MCP-1 expression.
[Mh] Termos MeSH primário: Quimiocina CCL2/metabolismo
Células Endoteliais/metabolismo
Proteína 1 Transportadora de Ânions Orgânicos/metabolismo
Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo
Uremia/metabolismo
[Mh] Termos MeSH secundário: Transporte Biológico
Linhagem Celular
Sobrevivência Celular/efeitos dos fármacos
Cresóis/metabolismo
Cresóis/toxicidade
Relação Dose-Resposta a Droga
Células Endoteliais/efeitos dos fármacos
Células Endoteliais/patologia
Seres Humanos
Indicã/metabolismo
Indicã/toxicidade
Proteína 1 Transportadora de Ânions Orgânicos/antagonistas & inibidores
Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores
Probenecid/farmacologia
Ésteres do Ácido Sulfúrico/metabolismo
Ésteres do Ácido Sulfúrico/toxicidade
Fatores de Tempo
Regulação para Cima
Uremia/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCL2 protein, human); 0 (Chemokine CCL2); 0 (Cresols); 0 (Organic Anion Transport Protein 1); 0 (Organic Anion Transporters, Sodium-Independent); 0 (Sulfuric Acid Esters); 0 (organic anion transport protein 3); 56M34ZQY1S (4-cresol sulfate); N187WK1Y1J (Indican); PO572Z7917 (Probenecid)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1159/000468542


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[PMID]:28447211
[Au] Autor:Tanabe Y; Shimizu C; Hamada A; Hashimoto K; Ikeda K; Nishizawa D; Hasegawa J; Shimomura A; Ozaki Y; Tamura N; Yamamoto H; Yunokawa M; Yonemori K; Takano T; Kawabata H; Tamura K; Fujiwara Y
[Ad] Endereço:Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
[Ti] Título:Paclitaxel-induced sensory peripheral neuropathy is associated with an ABCB1 single nucleotide polymorphism and older age in Japanese.
[So] Source:Cancer Chemother Pharmacol;79(6):1179-1186, 2017 Jun.
[Is] ISSN:1432-0843
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Whether age and inter-individual variability of pharmacogenetics are risk factors for paclitaxel-induced peripheral neuropathy (PIPN) is inconclusive. This study was conducted to evaluate the influence of previously investigated single nucleotide polymorphisms (SNPs) and age, using genotype data from a prospective study of paclitaxel-related toxicity in Japanese patients with breast cancer. METHODS: Peripheral blood mononuclear cells from 127 Japanese women with breast cancer who received weekly adjuvant paclitaxel were used to genotypes SLCO1B3 T334G (rs4149117), CYP2C8 A1196G (rs10509681), ABCB1 C1236T (rs1128503), ABCB1 G2677T/A (rs2032582), and ABCB1 C3435T (rs1045642). Genotypic and clinical factors were investigated for associations with PIPN. RESULTS: Of the five SNPs evaluated, no SNPs were significantly associated with grade 2 or higher PIPN. However, ABCB1 1236 TT showed a trend to associate with grade 2 or higher PIPN compared to ABCB1 CT/CC (odds ratio 2.1, 95% CI 0.991-4.548, p = 0.051). In subgroup analysis, patients ≥60 years old with an ABCB1 1236 TT had a higher incidence of ≥grade 2 PIPN compared to patients with CT or CC genotype (p = 0.027). On multivariable analysis, age ≥60 years and the ABCB1 1236 TT showed a significant association with ≥grade 2 PIPN (p = 0.005 and p = 0.034, respectively). CONCLUSIONS: ABCB1 1236 TT genotype and older age might be a predictor of PIPN, which diminishes quality of life of cancer survivors.
[Mh] Termos MeSH primário: Antineoplásicos Fitogênicos/efeitos adversos
Paclitaxel/efeitos adversos
Doenças do Sistema Nervoso Periférico/induzido quimicamente
Doenças do Sistema Nervoso Periférico/epidemiologia
[Mh] Termos MeSH secundário: Subfamília B de Transportador de Cassetes de Ligação de ATP/genética
Adulto
Idoso
Envelhecimento/genética
Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos
Neoplasias da Mama/complicações
Neoplasias da Mama/tratamento farmacológico
Citocromo P-450 CYP2C8/genética
Feminino
Genótipo
Seres Humanos
Incidência
Meia-Idade
Transportadores de Ânions Orgânicos Sódio-Independentes/genética
Farmacogenética
Polimorfismo de Nucleotídeo Único
Valor Preditivo dos Testes
Estudos Prospectivos
Células Receptoras Sensoriais
Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (ABCB1 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family B); 0 (Antineoplastic Agents, Phytogenic); 0 (Organic Anion Transporters, Sodium-Independent); 0 (SLCO1B3 protein, human); 0 (Solute Carrier Organic Anion Transporter Family Member 1B3); EC 1.14.14.1 (CYP2C8 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2C8); P88XT4IS4D (Paclitaxel)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170428
[St] Status:MEDLINE
[do] DOI:10.1007/s00280-017-3314-9


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[PMID]:28371506
[Au] Autor:Tanner C; Boocock J; Stahl EA; Dobbyn A; Mandal AK; Cadzow M; Phipps-Green AJ; Topless RK; Hindmarsh JH; Stamp LK; Dalbeth N; Choi HK; Mount DB; Merriman TR
[Ad] Endereço:University of Otago, Dunedin, New Zealand.
[Ti] Título:Population-Specific Resequencing Associates the ATP-Binding Cassette Subfamily C Member 4 Gene With Gout in New Zealand Maori and Pacific Men.
[So] Source:Arthritis Rheumatol;69(7):1461-1469, 2017 Jul.
[Is] ISSN:2326-5205
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: There is no evidence for a genetic association between organic anion transporters 1-3 (SLC22A6, SLC22A7, and SLC22A8) and multidrug resistance protein 4 (MRP4; encoded by ABCC4) with the levels of serum urate or gout. The Maori and Pacific (Polynesian) population of New Zealand has the highest prevalence of gout worldwide. The aim of this study was to determine whether any Polynesian population-specific genetic variants in SLC22A6-8 and ABCC4 are associated with gout. METHODS: All participants had ≥3 self-reported Maori and/or Pacific grandparents. Among the total sample set of 1,808 participants, 191 hyperuricemic and 202 normouricemic individuals were resequenced over the 4 genes, and the remaining 1,415 individuals were used for replication. Regression analyses were performed, adjusting for age, sex, and Polynesian ancestry. To study the functional effect of nonsynonymous variants of ABCC4, transport assays were performed in Xenopus laevis oocytes. RESULTS: A total of 39 common variants were detected, with an ABCC4 variant (rs4148500) significantly associated with hyperuricemia and gout. This variant was monomorphic for the urate-lowering allele in Europeans. There was evidence for an association of rs4148500 with gout in the resequenced samples (odds ratio [OR] 1.62 [P = 0.012]) that was replicated (OR 1.25 [P = 0.033]) and restricted to men (OR 1.43 [P = 0.001] versus OR 0.98 [P = 0.89] in women). The gout risk allele was associated with fractional excretion of uric acid in male individuals (ß = -0.570 [P = 0.01]). A rare population-specific allele (P1036L) with predicted strong functional consequence reduced the uric acid transport activity of ABCC4 by 30%. CONCLUSION: An association between ABCC4 and gout and fractional excretion of uric acid is consistent with the established role of MRP4 as a unidirectional renal uric acid efflux pump.
[Mh] Termos MeSH primário: Gota/genética
Hiperuricemia/genética
Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética
Grupo com Ancestrais Oceânicos/genética
[Mh] Termos MeSH secundário: Adulto
Animais
Western Blotting
Estudos de Casos e Controles
Feminino
Seres Humanos
Modelos Logísticos
Masculino
Meia-Idade
Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo
Nova Zelândia
Oócitos/metabolismo
Proteína 1 Transportadora de Ânions Orgânicos/genética
Transportadores de Ânions Orgânicos Sódio-Independentes/genética
Polimorfismo de Nucleotídeo Único
Análise de Sequência de DNA
Ácido Úrico/metabolismo
Ácido Úrico/urina
Xenopus laevis
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCC4 protein, human); 0 (Multidrug Resistance-Associated Proteins); 0 (Organic Anion Transport Protein 1); 0 (Organic Anion Transporters, Sodium-Independent); 0 (SLC22A7 protein, human); 0 (organic anion transport protein 3); 268B43MJ25 (Uric Acid)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170821
[Lr] Data última revisão:
170821
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170404
[St] Status:MEDLINE
[do] DOI:10.1002/art.40110



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