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[PMID]:28817838
[Au] Autor:Lévi F; Karaboué A; Saffroy R; Desterke C; Boige V; Smith D; Hebbar M; Innominato P; Taieb J; Carvalho C; Guimbaud R; Focan C; Bouchahda M; Adam R; Ducreux M; Milano G; Lemoine A
[Ad] Endereço:INSERM, UMRS 935 Team 'Cancer Chronotherapy and Postoperative Liver Function', Campus CNRS, 7 rue Guy Môquet, and UMRS 1193 'Physiopathology and treatment of Liver diseases', Paul Brousse Hospital, 14 avenue Paul-Vaillant-Couturier, 94800 Villejuif, France.
[Ti] Título:Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228).
[So] Source:Br J Cancer;117(7):965-973, 2017 Sep 26.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The hepatic artery infusion (HAI) of irinotecan, oxaliplatin and 5-fluorouracil with intravenous cetuximab achieved outstanding efficacy in previously treated patients with initially unresectable liver metastases from colorectal cancer. This planned study aimed at the identification of pharmacogenetic predictors of outcomes. METHODS: Circulating mononuclear cells were analysed for 207 single-nucleotide polymorphisms (SNPs) from 34 pharmacology genes. Single-nucleotide polymorphisms passing stringent Hardy-Weinberg equilibrium test were tested for their association with outcomes in 52 patients (male/female, 36/16; WHO PS, 0-1). RESULTS: VKORC1 SNPs (rs9923231 and rs9934438) were associated with early and objective responses, and survival. For rs9923231, T/T achieved more early responses than C/T (50% vs 5%, P=0.029) and greatest 4-year survival (46% vs 0%, P=0.006). N-acetyltransferase-2 (rs1041983 and rs1801280) were associated with up to seven-fold more macroscopically complete hepatectomies. Progression-free survival was largest in ABCB1 rs1045642 T/T (P=0.026) and rs2032582 T/T (P=0.035). Associations were found between toxicities and gene variants (P<0.05), including neutropenia with ABCB1 (rs1045642) and SLC0B3 (rs4149117 and rs7311358); and diarrhoea with CYP2C9 (rs1057910), CYP2C19 (rs3758581), UGT1A6 (rs4124874) and SLC22A1 (rs72552763). CONCLUSION: VKORC1, NAT2 and ABCB1 variants predicted for HAI efficacy. Pharmacogenetics could guide the personalisation of liver-targeted medico-surgical therapies.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Arilamina N-Acetiltransferase/genética
Neoplasias Colorretais/genética
Neoplasias Hepáticas/tratamento farmacológico
Neoplasias Hepáticas/genética
Vitamina K Epóxido Redutases/genética
[Mh] Termos MeSH secundário: Subfamília B de Transportador de Cassetes de Ligação de ATP/genética
Administração Intravenosa
Adulto
Idoso
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Camptotecina/administração & dosagem
Camptotecina/análogos & derivados
Proteínas da Membrana Plasmática de Transporte de Catecolaminas/genética
Cetuximab/administração & dosagem
Neoplasias Colorretais/patologia
Citocromo P-450 CYP2C19/genética
Citocromo P-450 CYP2C9/genética
Diarreia/induzido quimicamente
Diarreia/genética
Intervalo Livre de Doença
Feminino
Fluoruracila/administração & dosagem
Glucuronosiltransferase/genética
Hepatectomia
Artéria Hepática
Seres Humanos
Infusões Intra-Arteriais
Neoplasias Hepáticas/secundário
Neoplasias Hepáticas/cirurgia
Masculino
Meia-Idade
Neutropenia/induzido quimicamente
Neutropenia/genética
Compostos Organoplatínicos/administração & dosagem
Farmacogenética
Polimorfismo de Nucleotídeo Único
Taxa de Sobrevida
Resultado do Tratamento
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCB1 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family B); 0 (Catecholamine Plasma Membrane Transport Proteins); 0 (Organoplatinum Compounds); 0 (Slc22a1 protein, mouse); 04ZR38536J (oxaliplatin); 7673326042 (irinotecan); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.14.1 (Cytochrome P-450 CYP2C19); EC 1.17.4.4 (VKORC1 protein, human); EC 1.17.4.4 (Vitamin K Epoxide Reductases); EC 2.3.1.5 (Arylamine N-Acetyltransferase); EC 2.3.1.5 (NAT2 protein, human); EC 2.4.1.- (UDP-glucuronosyltransferase, UGT1A6); EC 2.4.1.17 (Glucuronosyltransferase); PQX0D8J21J (Cetuximab); U3P01618RT (Fluorouracil); XT3Z54Z28A (Camptothecin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2017.278


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[PMID]:27676604
[Au] Autor:Chen J; Brockmöller J; Seitz T; König J; Tzvetkov MV; Chen X
[Ti] Título:Tropane alkaloids as substrates and inhibitors of human organic cation transporters of the SLC22 (OCT) and the SLC47 (MATE) families.
[So] Source:Biol Chem;398(2):237-249, 2017 Feb 01.
[Is] ISSN:1437-4315
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Tropane alkaloids and their derivatives are anticholinergic drugs with narrow therapeutic range. Here we characterize the organic cation transporters from the SLC22 (OCT1, OCT2, and OCT3) and the SLC47 families (MATE1 and MATE2-K) as potential mediators of the renal and extra-renal excretion, the two major roads of elimination of these substances. All analyzed compounds inhibited and the quaternary amine derivatives ipratropium and trospium were strongly transported by OCTs and MATEs. Overexpression of OCTs or MATEs in HEK293 cells resulted in an up to 63-fold increase in the uptake of ipratropium (Km of 0.32 µm to OCT2 and Vmax of 3.34 nmol×mg protein-1×min-1 to MATE1). The transcellular transport of ipratropium was 16-fold higher in OCT2-MATE1 and 10-fold higher in OCT1-MATE1 overexpressing compared to control MDCKII cells. Genetic polymorphisms in OCT1 and OCT2 affected ipratropium uptake and clinically relevant concentration of ondansetron and pyrithiamine inhibited ipratropium uptake via MATEs by more than 90%. This study suggests that OCT1, OCT2 and MATEs may be strongly involved in the renal and extra-renal elimination of ipratropium and other quaternary amine alkaloids. These substances have a notoriously narrow therapeutic range and the drug-drug interactions suggested here should be further critically evaluated in humans.
[Mh] Termos MeSH primário: Proteínas da Membrana Plasmática de Transporte de Catecolaminas/antagonistas & inibidores
Proteínas da Membrana Plasmática de Transporte de Catecolaminas/metabolismo
Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores
Proteínas de Transporte de Cátions Orgânicos/metabolismo
Tropanos/metabolismo
Tropanos/farmacologia
[Mh] Termos MeSH secundário: Animais
Transporte Biológico/efeitos dos fármacos
Proteínas da Membrana Plasmática de Transporte de Catecolaminas/genética
Permeabilidade da Membrana Celular/efeitos dos fármacos
Cães
Interações Medicamentosas
Células HEK293
Seres Humanos
Ipratrópio/metabolismo
Células Madin Darby de Rim Canino
Proteínas de Transporte de Cátions Orgânicos/genética
Polimorfismo de Nucleotídeo Único
Tropanos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Catecholamine Plasma Membrane Transport Proteins); 0 (Organic Cation Transport Proteins); 0 (Tropanes); GR88G0I6UL (Ipratropium)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160928
[St] Status:MEDLINE


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[PMID]:27621243
[Au] Autor:Paschou SA; Vryonidou A; Goulis DG
[Ad] Endereço:Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece; Department of Endocrinology and Diabetes, Hellenic Red Cross Hospital, Athens, Greece.
[Ti] Título:Adrenal incidentalomas: A guide to assessment, treatment and follow-up.
[So] Source:Maturitas;92:79-85, 2016 10.
[Is] ISSN:1873-4111
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Adrenal incidentalomas are clinically unsuspected lesions that are detected in adrenal glands during imaging procedures for other causes. With widespread use of imaging - both computed tomography (CT) and magnetic resonance imaging (MRI) - adrenal incidentalomas are now a common clinical problem. The two main clinical issues to be determined in this setting are the risk of malignancy and the hormonal activity of these lesions. The answers to these two questions, along with the clinical characteristics of each individual patient and co-morbidities, will guide the treatment strategy, which can vary from simple follow-up to surgical resection. The objective of this article is to present updated information on the definition, prevalence, imaging and functional features of adrenal incidentalomas and to provide a guide to their optimal assessment, treatment and follow-up. This review collected, analyzed and qualitatively re-synthesized information regarding: (1) the various clinical entities known as "adrenal incidentalomas", (2) the initial assessment of risk of malignancy, (3) the initial assessment of whether the lesion is hormonally active or non-functioning, (4) the absolute and relative indications for surgical treatment, (5) the follow-up of patients who are not deemed to need surgical treatment after initial assessment, and (6) the post-operative follow-up of patients who undergo surgical treatment. The evidence calls for clinicians to bear in mind the Hippocratian advice "ωϕελέειν ή µÎ· ßλάπτειν" ("first do no harm").
[Mh] Termos MeSH primário: Neoplasias das Glândulas Suprarrenais/secreção
Neoplasias das Glândulas Suprarrenais/terapia
[Mh] Termos MeSH secundário: Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem
Neoplasias das Glândulas Suprarrenais/patologia
Assistência ao Convalescente
Aldosterona/secreção
Proteínas da Membrana Plasmática de Transporte de Catecolaminas/secreção
Seres Humanos
Hidrocortisona/secreção
Achados Incidentais
Imagem por Ressonância Magnética
Meia-Idade
Tomografia Computadorizada por Raios X
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Catecholamine Plasma Membrane Transport Proteins); 4964P6T9RB (Aldosterone); WI4X0X7BPJ (Hydrocortisone)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170828
[Lr] Data última revisão:
170828
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160914
[St] Status:MEDLINE


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[PMID]:27063863
[Au] Autor:Fan PW; Chen JZ; Allan Jaochico M; La H; Liu N; Mulder T; Cass RT; Durk M; Messick K; Valle N; Liu S; Lee W; Crawford JJ; Rudolf J; Murray LJ; Cyrus Khojasteh S; Wright M
[Ad] Endereço:Genentech, Inc. 1 DNA Way, MS 412a, South San Francisco, CA 94080, USA. fan.peter@gene.com.
[Ti] Título:Rate-Determining and Rate-Limiting Steps in the Clearance and Excretion of a Potent and Selective p21-Activated Kinase Inhibitor: A Case Study of Rapid Hepatic Uptake and Slow Elimination in Rat.
[So] Source:Drug Metab Lett;10(2):91-100, 2016.
[Is] ISSN:1874-0758
[Cp] País de publicação:United Arab Emirates
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Significant under-prediction of in vivo clearance in rat was observed for a potent p21-activated kinase (PAK1) inhibitor, GNE1. OBJECTIVE: Rate-determining (rapid uptake) and rate-limiting (slow excretion) steps in systemic clearance and elimination of GNE1, respectively, were evaluated to better understand the cause of the in vitro-in vivo (IVIV) disconnect. METHODS: A series of in vivo, ex vivo, and in vitro experiments were carried out: 1) the role of organic cation transporters (Oct or Slc22a) was investigated in transporter knock-out and wild-type animals with or without 1-aminobenzotriazole (ABT) pretreatment; 2) the concentration-dependent hepatic extraction ratio was determined in isolated perfused rat liver; and 3) excreta were collected from both bile duct cannulated and non-cannulated rats after intravenous injection. RESULTS: After intravenous dosing, the rate-determining step in clearance was found to be mediated by the active uptake transporter, Oct1. In cannulated rats, biliary and renal clearance of GNE1 accounted for only approximately 14 and 16% of the total clearance, respectively. N-acetylation, an important metabolic pathway, accounted for only about 10% of the total dose. In non-cannulated rats, the majority of the dose was recovered in feces as unchanged parent (up to 91%) overnight following intravenous administration. CONCLUSION: Because the clearance of GNE1 is mediated through uptake transporters rather than metabolism, the extrahepatic expression of Oct1 in kidney and intestine in rat likely plays an important role in the IVIV disconnect in hepatic clearance prediction. The slow process of intestinal secretion is the rate-limiting step for in vivo clearance of GNE1.
[Mh] Termos MeSH primário: Proteínas da Membrana Plasmática de Transporte de Catecolaminas/metabolismo
Fígado/metabolismo
Inibidores de Proteínas Quinases/farmacocinética
Pirazóis/farmacocinética
Pirimidinas/farmacocinética
Quinases Ativadas por p21/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Proteínas da Membrana Plasmática de Transporte de Catecolaminas/genética
Feminino
Masculino
Camundongos
Camundongos Knockout
Proteínas de Transporte de Cátions Orgânicos/metabolismo
Ratos
Ratos Sprague-Dawley
Triazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Catecholamine Plasma Membrane Transport Proteins); 0 (GNE1 compound); 0 (Organic Cation Transport Proteins); 0 (Protein Kinase Inhibitors); 0 (Pyrazoles); 0 (Pyrimidines); 0 (Slc22a1 protein, rat); 0 (Triazoles); 1614-12-6 (1-aminobenzotriazole); EC 2.7.11.1 (p21-Activated Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160412
[St] Status:MEDLINE


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[PMID]:25588984
[Au] Autor:Ljubojevic M; Breljak D; Herak-Kramberger CM; Anzai N; Sabolic I
[Ad] Endereço:Molecular Toxicology Unit, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, 10000, Zagreb, Croatia.
[Ti] Título:Expression of basolateral organic anion and cation transporters in experimental cadmium nephrotoxicity in rat kidney.
[So] Source:Arch Toxicol;90(3):525-41, 2016 Mar.
[Is] ISSN:1432-0738
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Cadmium (Cd)-intoxicated experimental animals exhibit impaired renal secretion of organic anions (OA) and cations (OC), indicating their transporters (Oats and Octs) in the proximal tubule (PT) basolateral membrane as possible targets of Cd. To correlate transport data from the literature with the expression of relevant transporters, we performed immunochemical and RT-PCR studies of renal Oats and Octs in the subchronic (treatment with CdCl2; 2 mg Cd/kg b.m./day, for 2 weeks) and acute (treatment with Cd-metallothionein (CdMT); 0.4 mg Cd/kg b.m., 6 or 12 h before killing) models of Cd nephrotoxicity. In the subchronic model, PT exhibited a minor loss of basolateral invaginations and overall unchanged expression of Na(+)/K(+)-ATPase and GAPDH proteins and mRNAs, while the expression of Oat and Oct proteins and their mRNAs was strongly downregulated. In the acute model, a time-related redistribution of basolateral transporters to the intracellular vesicular compartment was a major finding. However, 6 h following CdMT treatment, the total abundance of Oat and Oct proteins in the renal tissue remained unchanged, the expression of mRNAs decreased only for Oats, while a limited Oat1 and Na(+)/K(+)-ATPase immunoreactivity in the PT apical membrane indicated loss of cell polarity. As tested in rats treated with colchicine, the observed loss/redistribution of basolateral transporters in both models may be independent on microtubules. Therefore, the diminished renal secretion of OA and OC via PT in Cd nephrotoxicity may result from (a) limited loss of secretory surface (basolateral invaginations), (b) selective loss of Oats and Octs, and
[Mh] Termos MeSH primário: Cádmio/toxicidade
Nefropatias/induzido quimicamente
Transportadores de Ânions Orgânicos/metabolismo
Proteínas de Transporte de Cátions Orgânicos/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteínas da Membrana Plasmática de Transporte de Catecolaminas/genética
Proteínas da Membrana Plasmática de Transporte de Catecolaminas/metabolismo
Rim/efeitos dos fármacos
Rim/metabolismo
Rim/patologia
Nefropatias/metabolismo
Túbulos Renais Proximais/metabolismo
Masculino
Metalotioneína/toxicidade
Proteína 1 Transportadora de Ânions Orgânicos/genética
Proteína 1 Transportadora de Ânions Orgânicos/metabolismo
Transportadores de Ânions Orgânicos/genética
Proteínas de Transporte de Cátions Orgânicos/genética
Ratos Wistar
ATPase Trocadora de Sódio-Potássio/metabolismo
Testes de Toxicidade Aguda
Testes de Toxicidade Subcrônica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Catecholamine Plasma Membrane Transport Proteins); 0 (Organic Anion Transport Protein 1); 0 (Organic Anion Transporters); 0 (Organic Cation Transport Proteins); 0 (Slc22a1 protein, rat); 0 (Slc22a6 protein, rat); 0 (cadmium-binding protein); 00BH33GNGH (Cadmium); 9038-94-2 (Metallothionein); EC 3.6.3.9 (Sodium-Potassium-Exchanging ATPase)
[Em] Mês de entrada:1611
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150116
[St] Status:MEDLINE
[do] DOI:10.1007/s00204-015-1450-8


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[PMID]:26187454
[Au] Autor:Santana MM; Rosmaninho-Salgado J; Cortez V; Pereira FC; Kaster MP; Aveleira CA; Ferreira M; Álvaro AR; Cavadas C
[Ad] Endereço:CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
[Ti] Título:Impaired adrenal medullary function in a mouse model of depression induced by unpredictable chronic stress.
[So] Source:Eur Neuropsychopharmacol;25(10):1753-66, 2015 Oct.
[Is] ISSN:1873-7862
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Stress has been considered determinant in the etiology of depression. The adrenal medulla plays a key role in response to stress by releasing catecholamines, which are important to maintain homeostasis. We aimed to study the adrenal medulla in a mouse model of depression induced by 21 days of unpredictable chronic stress (UCS). We observed that UCS induced a differential and time-dependent change in adrenal medulla. After 7 days of UCS, mice did not show depressive-like behavior, but the adrenal medullae show increased protein and/or mRNA levels of catecholamine biosynthetic enzymes (TH, DßH and PNMT), Neuropeptide Y, the SNARE protein SNAP-25, the catecholamine transporter VMAT2 and the chromaffin progenitor cell markers, Mash1 and Phox2b. Moreover, 7 days of UCS induced a decrease in the chromaffin progenitor cell markers, Sox9 and Notch1. This suggests an increased capacity of chromaffin cells to synthesize, store and release catecholamines. In agreement, after 7 days, UCS mice had higher NE and EP levels in adrenal medulla. Opposite, when mice were submitted to 21 days of UCS, and showed a depressive like behavior, adrenal medullae had lower protein and/or mRNA levels of catecholamine biosynthetic enzymes (TH, DßH, PNMT), catecholamine transporters (NET, VMAT1), SNARE proteins (synthaxin1A, SNAP25, VAMP2), catecholamine content (EP, NE), and lower EP serum levels, indicating a reduction in catecholamine synthesis, re-uptake, storage and release. In conclusion, this study suggests that mice exposed to UCS for a period of 21 days develop a depressive-like behavior accompanied by an impairment of adrenal medullary function.
[Mh] Termos MeSH primário: Medula Suprarrenal/fisiopatologia
Transtorno Depressivo/fisiopatologia
Estresse Psicológico/fisiopatologia
[Mh] Termos MeSH secundário: Medula Suprarrenal/patologia
Animais
Peso Corporal
Proteínas da Membrana Plasmática de Transporte de Catecolaminas/metabolismo
Catecolaminas/metabolismo
Grânulos Cromafim/fisiologia
Doença Crônica
Corticosterona/sangue
Transtorno Depressivo/patologia
Modelos Animais de Doenças
Masculino
Camundongos Endogâmicos C57BL
Atividade Motora/fisiologia
Tamanho do Órgão
RNA Mensageiro/metabolismo
Células-Tronco/fisiologia
Estresse Psicológico/patologia
Incerteza
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Catecholamine Plasma Membrane Transport Proteins); 0 (Catecholamines); 0 (RNA, Messenger); W980KJ009P (Corticosterone)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:151010
[Lr] Data última revisão:
151010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150719
[St] Status:MEDLINE


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[PMID]:25712368
[Au] Autor:Xu Q; Wang C; Liu Q; Meng Q; Sun H; Peng J; Sun P; Huo X; Liu K
[Ad] Endereço:Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China.
[Ti] Título:Decreased liver distribution of entecavir is related to down-regulation of Oat2/Oct1 and up-regulation of Mrp1/2/3/5 in rat liver fibrosis.
[So] Source:Eur J Pharm Sci;71:73-9, 2015 Apr 25.
[Is] ISSN:1879-0720
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: We aimed to elucidate whether entecavir was taken-up into liver by transporters and clarify the possible molecular mechanisms of changes in the distribution of entecavir in rat liver fibrosis. METHODS: Thioacetamide (TAA) was applied to induce rat liver fibrosis. Samples of liver uptake index (LUI) study and uptake of entecavir in isolated rat hepatocytes were determined by LC-MS/MS. qRT-PCR and western blotting were used to examine the expression of transporters in rat liver. RESULTS: The uptake of entecavir in hepatocytes was significantly higher at 37 °C compared to 4 °C. Furthermore, TEA and PAH could inhibit significantly the uptake of entecavir by the hepatocytes. It indicated that Oat2 and Oct1 were contributed to uptake of entecavir. Compared with control group, LUI and the uptake of entecavir, PAH and TEA in hepatocytes were significantly reduced in liver fibrosis group. Further study indicated that entecavir Vmax in liver fibrosis group was significantly decreased while the Km was not changed. These results indicated that transport capacity TAA treated isolated rat liver hepatocytes were reduced. Oat2 and Oct1 expressions were down-regulated and Mrp1/2/3/5 mRNA expressions were up-regulated in liver fibrosis group. CONCLUSIONS: The changes of these transporters were contributed to decrease liver distribution of entecavir.
[Mh] Termos MeSH primário: Antivirais/farmacologia
Proteínas da Membrana Plasmática de Transporte de Catecolaminas/genética
Guanina/análogos & derivados
Fígado/efeitos dos fármacos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética
Transportadores de Ânions Orgânicos Sódio-Independentes/genética
[Mh] Termos MeSH secundário: Alanina Transaminase/sangue
Animais
Antivirais/farmacocinética
Aspartato Aminotransferases/sangue
Proteínas da Membrana Plasmática de Transporte de Catecolaminas/metabolismo
Regulação para Baixo
Fibrose
Guanina/farmacocinética
Guanina/farmacologia
Fígado/metabolismo
Fígado/patologia
Masculino
Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo
Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo
RNA Mensageiro/metabolismo
Ratos Wistar
Tioacetamida
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (Catecholamine Plasma Membrane Transport Proteins); 0 (Multidrug Resistance-Associated Proteins); 0 (Organic Anion Transporters, Sodium-Independent); 0 (RNA, Messenger); 0 (Slc22a1 protein, rat); 0 (Slc22a7 protein, rat); 075T165X8M (Thioacetamide); 5968Y6H45M (entecavir); 5Z93L87A1R (Guanine); EC 2.6.1.1 (Aspartate Aminotransferases); EC 2.6.1.2 (Alanine Transaminase)
[Em] Mês de entrada:1512
[Cu] Atualização por classe:150318
[Lr] Data última revisão:
150318
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150226
[St] Status:MEDLINE


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[PMID]:25701312
[Au] Autor:Kato K; Moriyama C; Ito N; Zhang X; Hachiuma K; Hagima N; Iwata K; Yamaguchi J; Maeda K; Ito K; Suzuki H; Sugiyama Y; Kusuhara H
[Ad] Endereço:Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama, Japan.
[Ti] Título:Involvement of organic cation transporters in the clearance and milk secretion of thiamine in mice.
[So] Source:Pharm Res;32(7):2192-204, 2015 Jul.
[Is] ISSN:1573-904X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: To investigate the role of organic cation transporters (Octs) and multidrug and toxin extrusion protein 1 (Mate1) in the disposition of thiamine. METHODS: The uptake of [(3)H]thiamine was determined in Oct1-, Oct2-, and Oct3-expressing HEK293 cells and freshly isolated hepatocytes. A pharmacokinetic study of thiamine-d3 following intravenous infusion (1 and 100 nmol/min/kg) was conducted in male Oct1/2(+/+) and Oct1/2(-/-) mice. A MATE inhibitor, pyrimethamine, (5 mg/kg) was administered intravenously. The plasma and breast milk concentrations of thiamine were determined in female mice. RESULTS: Thiamine is a substrate of Oct1 and Oct2, but not Oct3. Oct1/2 defect caused a significant reduction in the uptake of [(3)H]thiamine by hepatocytes in vitro, and elevated the plasma thiamine concentration by 5.8-fold in vivo. The plasma clearance of thiamine-d3 was significantly decreased in Oct1/2(-/-) mice. At the higher infusion rate of 100 nmol/min/kg thiamine-d3, Oct1/2 defect or pyrimethamine-treatment caused a significant reduction in the renal clearance of thiamine-d3. The total thiamine and thiamine-d3 concentrations were moderately reduced in the intestine of Oct1/2(-/-) mice but were unchanged in the kidney, liver, or brain. The milk-to-plasma concentration ratio of thiamine was decreased by 28-fold in the Oct1/2(-/-) mice. CONCLUSIONS: Oct1 is possibly responsible for the plasma clearance of thiamine via tissue uptake and for milk secretion. Oct1/2 and Mate1 are involved in the renal tubular secretion of thiamine.
[Mh] Termos MeSH primário: Proteínas da Membrana Plasmática de Transporte de Catecolaminas/metabolismo
Hepatócitos/metabolismo
Leite/secreção
Proteínas de Transporte de Cátions Orgânicos/metabolismo
Tiamina/farmacocinética
[Mh] Termos MeSH secundário: Animais
Transporte Biológico
Proteínas da Membrana Plasmática de Transporte de Catecolaminas/genética
Cromatografia Líquida
Células HEK293
Seres Humanos
Masculino
Taxa de Depuração Metabólica
Camundongos Knockout
Proteínas de Transporte de Cátions Orgânicos/genética
Espectrometria de Massas em Tandem
Tiamina/sangue
Tiamina/secreção
Distribuição Tecidual
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Catecholamine Plasma Membrane Transport Proteins); 0 (MATE1 protein, mouse); 0 (Organic Cation Transport Proteins); 0 (Slc22a1 protein, mouse); X66NSO3N35 (Thiamine)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150222
[St] Status:MEDLINE
[do] DOI:10.1007/s11095-014-1608-8


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[PMID]:25651155
[Au] Autor:Spasojevic N; Jovanovic P; Dronjak S
[Ad] Endereço:Institute of Nuclear Sciences Vinca, Department of Molecular Biology and Endocrinology, University of Belgrade, Belgrade, Serbia.
[Ti] Título:Differential regulation of catecholamine synthesis and transport in rat adrenal medulla by fluoxetine treatment.
[So] Source:An Acad Bras Cienc;87(1):343-50, 2015 Mar.
[Is] ISSN:1678-2690
[Cp] País de publicação:Brazil
[La] Idioma:eng
[Ab] Resumo:We have recently shown that chronic fluoxetine treatment acted significantly increasing plasma norepinephrine and epinephrine concentrations both in control and chronically stressed adult male rats. However, possible effects of fluoxetine on catecholamine synthesis and re-uptake in adrenal medulla have been largely unknown. In the present study the effects of chronic fluoxetine treatment on tyrosine hydroxylase, a rate-limiting enzyme in catecholamine synthesis, as well as a norepinephrine transporter and vesicular monoamine transporter 2 gene expressions in adrenal medulla of animals exposed to chronic unpredictable mild stress (CUMS) for 4 weeks, were investigated. Gene expression analyses were performed using a real-time quantitative reverse transcription-PCR. Chronically stressed animals had increased tyrosine hydroxylase mRNA levels and decreased expression of both transporters. Fluoxetine increased tyrosine hydroxylase and decreased norepinephrine transporter gene expression in both unstressed and CUMS rats. These findings suggest that chronic fluoxetine treatment increased plasma catecholamine levels by affecting opposing changes in catecholamine synthesis and uptake.
[Mh] Termos MeSH primário: Medula Suprarrenal/metabolismo
Antidepressivos de Segunda Geração/farmacologia
Proteínas da Membrana Plasmática de Transporte de Catecolaminas/metabolismo
Catecolaminas/biossíntese
Fluoxetina/farmacologia
Proteínas Vesiculares de Transporte de Monoamina/metabolismo
[Mh] Termos MeSH secundário: Animais
Epinefrina/metabolismo
Masculino
Norepinefrina/metabolismo
Ratos
Ratos Wistar
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Estresse Psicológico
Tirosina 3-Mono-Oxigenase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antidepressive Agents, Second-Generation); 0 (Catecholamine Plasma Membrane Transport Proteins); 0 (Catecholamines); 0 (Vesicular Monoamine Transport Proteins); 01K63SUP8D (Fluoxetine); EC 1.14.16.2 (Tyrosine 3-Monooxygenase); X4W3ENH1CV (Norepinephrine); YKH834O4BH (Epinephrine)
[Em] Mês de entrada:1601
[Cu] Atualização por classe:150326
[Lr] Data última revisão:
150326
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150205
[St] Status:MEDLINE


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[PMID]:25359200
[Au] Autor:Kwon M; Choi YA; Choi MK; Song IS
[Ad] Endereço:College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Dae-gu, 702-701, Korea.
[Ti] Título:Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin.
[So] Source:Arch Pharm Res;38(5):849-56, 2015.
[Is] ISSN:0253-6269
[Cp] País de publicação:Korea (South)
[La] Idioma:eng
[Ab] Resumo:Berberine, the main active component of the herbal medicine Rhizoma Coptidis, has been reported to have hypoglycemic and insulin-sensitizing effects and, therefore, could be combined with metformin therapy. Thus, we assessed the potential drug-drug interactions between berberine and metformin. We investigated the in vitro inhibitory potency of berberine on metformin uptake in HEK293 cells overexpressing organic cation transporter (OCT) 1 and 2. To investigate whether this inhibitory effect of berberine on OCT1 and OCT2 could change the pharmacokinetics of metformin in vivo, we measured the effect of berberine co-administration on the pharmacokinetics of metformin at a single intravenous dose of 2 mg/kg metformin and 10 mg/kg berberine. In HEK293 cells, berberine inhibited OCT1- and OCT2-mediated metformin uptake in a concentration dependent manner and IC50 values for OCT1 and OCT2 were 7.28 and 11.3 µM, respectively. Co-administration of berberine increased the initial plasma concentration and AUC of metformin and decreased systemic clearance and volume of distribution of metformin in rats, suggesting that berberine inhibited disposition of metformin, which is governed by OCT1 and OCT2. Berberine inhibited the transport activity of OCT1 and OCT2 and showed significant potential drug-drug interactions with metformin in in vivo rats.
[Mh] Termos MeSH primário: Berberina/sangue
Proteínas da Membrana Plasmática de Transporte de Catecolaminas/fisiologia
Metformina/sangue
Proteínas de Transporte de Cátions Orgânicos/fisiologia
[Mh] Termos MeSH secundário: Administração Intravenosa
Animais
Berberina/administração & dosagem
Interações Medicamentosas/fisiologia
Células HEK293
Seres Humanos
Masculino
Metformina/administração & dosagem
Transportador 2 de Cátion Orgânico
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Catecholamine Plasma Membrane Transport Proteins); 0 (Organic Cation Transport Proteins); 0 (Organic Cation Transporter 2); 0 (Slc22a1 protein, rat); 0 (Slc22a2 protein, rat); 0I8Y3P32UF (Berberine); 9100L32L2N (Metformin)
[Em] Mês de entrada:1602
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141101
[St] Status:MEDLINE
[do] DOI:10.1007/s12272-014-0510-6



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