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1.
Phys Rev Lett ; 122(21): 217204, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31283322

RESUMO

We report a longitudinal spin Seebeck effect (SSE) study in epitaxially grown FeF_{2}(110) antiferromagnetic (AFM) thin films with strong uniaxial anisotropy over the temperature range of 3.8-250 K. Both the magnetic-field and temperature-dependent SSE signals below the Néel temperature (T_{N}=70 K) of the FeF_{2} films are consistent with a theoretical model based on the excitations of AFM magnons without any net induced static magnetic moment. In addition to the characteristic low-temperature SSE peak associated with the AFM magnons, there is another SSE peak at T_{N} which extends well into the paramagnetic phase. All the SSE data taken at different magnetic fields up to 12 T near and above the critical point T_{N} follow the critical scaling law very well with the critical exponents for magnetic susceptibility of 3D Ising systems, which suggests that the AFM spin correlation is responsible for the observed SSE near T_{N}.

2.
J Med Chem ; 62(5): 2265-2285, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30785748

RESUMO

Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P1 receptor modulator. In comparison to fingolimod (1), a full agonist of S1P1 currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life ( T1/2) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P1. Herein, we describe our efforts to discover highly potent, partial agonists of S1P1 with a shorter T1/2 and increased in vivo phosphate metabolite formation. These efforts culminated in the discovery of BMS-986166 (14a), which was advanced to human clinical evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments are discussed. Furthermore, efficacy of 14a in multiple preclinical models of autoimmune diseases are presented.

3.
J Community Psychol ; 46(7): 871-884, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30565737

RESUMO

This study surveyed 347 lesbian, gay, bisexual, transgender, and questioning college students from across the United States concerning their bully victimization, depressive symptoms, and sources of support. Participants responded to an online survey that asked them about their victimization experiences during the 3 months prior to the survey. The results indicate that four types of bully victimization (verbal, relational, cyber, and physical) occur during the college years, and that victimization relates positively to depressive symptomatology in sexual minority college students. The 4 forms of bullying did not relate to depression in the same manner for each of the 5 sexual minority subgroups. Peer support, but not family and campus support, provided a buffer against depression for lesbian, gay, and bisexual students. This study involved a sample exclusively comprising sexual minority college students, and the findings show the need for colleges to address bully victimization and its effects in this population.


Assuntos
Bullying/psicologia , Vítimas de Crime/psicologia , Depressão/psicologia , Minorias Sexuais e de Gênero/psicologia , Estudantes/psicologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Fatores de Proteção , Apoio Social , Estados Unidos , Universidades , Adulto Jovem
4.
Drug Metab Dispos ; 44(2): 238-49, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26608080

RESUMO

Organic cation transporter (OCT) 2, multidrug and toxin extrusion protein (MATE) 1, and MATE2K mediate the renal secretion of various cationic drugs and can serve as the loci of drug-drug interactions (DDI). To support the evaluation of cynomolgus monkey as a surrogate model for studying human organic cation transporters, monkey genes were cloned and shown to have a high degree of amino acid sequence identity versus their human counterparts (93.7, 94.7, and 95.4% for OCT2, MATE1, and MATE2K, respectively). Subsequently, the three transporters were individually stably expressed in human embryonic kidney (HEK) 293 cells and their properties (substrate selectivity, time course, pH dependence, and kinetics) were found to be comparable to the corresponding human form. For example, six known human cation transporter inhibitors, including pyrimethamine (PYR), showed generally similar IC50 values against the monkey transporters (within sixfold). Consistent with the in vitro inhibition of metformin (MFM) transport by PYR (IC50 for cynomolgus OCT2, MATE1, and MATE2K; 1.2 ± 0.38, 0.17 ± 0.04, and 0.25 ± 0.04 µM, respectively), intravenous pretreatment of monkeys with PYR (0.5 mg/kg) decreased the clearance (54 ± 9%) and increased in the area under the plasma concentration-time curve of MFM (AUC ratio versus control = 2.23; 90% confidence interval of 1.57 to 3.17). These findings suggest that the cynomolgus monkey may have some utility in support of in vitro-in vivo extrapolations (IVIVEs) involving the inhibition of renal OCT2 and MATEs. In turn, cynomolgus monkey-enabled IVIVEs may inform human DDI risk assessment.


Assuntos
Cátions/metabolismo , Rim/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Animais , Linhagem Celular , Interações de Medicamentos/fisiologia , Células HEK293 , Humanos , Cinética , Macaca fascicularis , Metformina/metabolismo , Pirimetamina/metabolismo
5.
Drug Metab Dispos ; 43(7): 984-93, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25904762

RESUMO

The contribution of organic anion transporter OAT2 (SLC22A7) to the renal tubular secretion of creatinine and its exact localization in the kidney are reportedly controversial. In the present investigation, the transport of creatinine was assessed in human embryonic kidney (HEK) cells that stably expressed human OAT2 (OAT2-HEK) and isolated human renal proximal tubule cells (HRPTCs). The tubular localization of OAT2 in human, monkey, and rat kidney was characterized. The overexpression of OAT2 significantly enhanced the uptake of creatinine in OAT2-HEK cells. Under physiologic conditions (creatinine concentrations of 41.2 and 123.5 µM), the initial rate of OAT2-mediated creatinine transport was approximately 11-, 80-, and 80-fold higher than OCT2, multidrug and toxin extrusion protein (MATE)1, and MATE2K, respectively, resulting in approximately 37-, 1850-, and 80-fold increase of the intrinsic transport clearance when normalized to the transporter protein concentrations. Creatinine intracellular uptake and transcellular transport in HRPTCs were decreased in the presence of 50 µM bromosulfophthalein and 100 µM indomethacin, which inhibited OAT2 more potently than other known creatinine transporters, OCT2 and multidrug and toxin extrusion proteins MATE1 and MATE2K (IC50: 1.3 µM vs. > 100 µM and 2.1 µM vs. > 200 µM for bromosulfophthalein and indomethacin, respectively) Immunohistochemistry analysis showed that OAT2 protein was localized to both basolateral and apical membranes of human and cynomolgus monkey renal proximal tubules, but appeared only on the apical membrane of rat proximal tubules. Collectively, the findings revealed the important role of OAT2 in renal secretion and possible reabsorption of creatinine and suggested a molecular basis for potential species difference in the transporter handling of creatinine.


Assuntos
Creatinina/metabolismo , Túbulos Renais/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Animais , Antiporters/metabolismo , Células HEK293 , Humanos , Imuno-Histoquímica , Indometacina/farmacologia , Túbulos Renais Proximais/metabolismo , Cinética , Macaca fascicularis , Masculino , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Sulfobromoftaleína/farmacologia
6.
J Pharmacol Exp Ther ; 344(3): 673-85, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23297161

RESUMO

Organic anion-transporting polypeptides (OATP) 1B1, 1B3, and 2B1 can serve as the loci of drug-drug interactions (DDIs). In the present work, the cynomolgus monkey was evaluated as a potential model for studying OATP-mediated DDIs. Three cynomolgus monkey OATPs (cOATPs), with a high degree of amino acid sequence identity (91.9, 93.5, and 96.6% for OATP1B1, 1B3, and 2B1, respectively) to their human counterparts, were cloned, expressed, and characterized. The cOATPs were stably transfected in human embryonic kidney cells and were functionally similar to the corresponding human OATPs (hOATPs), as evident from the similar uptake rate of typical substrates (estradiol-17ß-d-glucuronide, cholecystokinin octapeptide, and estrone-3-sulfate). Moreover, six known hOATP inhibitors exhibited similar IC(50) values against cOATPs. To further evaluate the appropriateness of the cynomolgus monkey as a model, a known hOATP substrate [rosuvastatin (RSV)]-inhibitor [rifampicin (RIF)] pair was examined in vitro; the monkey-derived parameters (RSV K(m) and RIF IC(50)) were similar (within 3.5-fold) to those obtained with hOATPs and human primary hepatocytes. In vivo, the area under the plasma concentration-time curve of RSV (3 mg/kg, oral) given 1 hour after a single RIF dose (15 mg/kg, oral) was increased 2.9-fold in cynomolgus monkeys, consistent with the value (3.0-fold) reported in humans. A number of in vitro-in vivo extrapolation approaches, considering the fraction of the pathways affected and free versus total inhibitor concentrations, were also explored. It is concluded that the cynomolgus monkey has the potential to serve as a useful model for the assessment of OATP-mediated DDIs in a nonclinical setting.


Assuntos
Fígado/metabolismo , Macaca fascicularis/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Animais , Transporte Biológico , Linhagem Celular , Clonagem Molecular/métodos , Interações de Medicamentos , Fluorbenzenos/farmacologia , Células HEK293 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Concentração Inibidora 50 , Fígado/efeitos dos fármacos , Masculino , Modelos Animais , Transportadores de Ânions Orgânicos/genética , Pirimidinas/farmacologia , Rifampina/farmacologia , Rosuvastatina Cálcica , Sulfonamidas/farmacologia
7.
Drug Metab Dispos ; 40(9): 1698-711, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22648560

RESUMO

Six proton pump inhibitors (PPIs), omeprazole, lansoprazole, esomeprazole, dexlansoprazole, pantoprazole, and rabeprazole, were shown to be weak inhibitors of cytochromes P450 (CYP3A4, -2B6, -2D6, -2C9, -2C8, and -1A2) in human liver microsomes. In most cases, IC50 values were greater than 40 µM, except for dexlansoprazole and lansoprazole with CYP1A2 (IC50 = ∼8 µM) and esomeprazole with CYP2C8 (IC50 = 31 µM). With the exception of CYP2C19 inhibition by omeprazole and esomeprazole (IC50 ratio, 2.5 to 5.9), there was no evidence for a marked time-dependent shift in IC50 (IC50 ratio, ≤ 2) after a 30-min preincubation with NADPH. In the absence of preincubation, lansoprazole (IC50 = 0.73 µM) and esomeprazole (IC50 = 3.7 µM) were the most potent CYP2C19 inhibitors, followed by dexlansoprazole and omeprazole (IC50 = ∼7.0 µM). Rabeprazole and pantoprazole (IC50 = ≥ 25 µM) were the weakest. A similar ranking was obtained with recombinant CYP2C19. Despite the IC50 ranking, after consideration of plasma levels (static and dynamic), protein binding, and metabolism-dependent inhibition, it is concluded that omeprazole and esomeprazole are the most potent CYP2C19 inhibitors. This was confirmed after the incubation of the individual PPIs with human primary hepatocytes (in the presence of human serum) and by monitoring their impact on diazepam N-demethylase activity at a low concentration of diazepam (2 µM). Data described herein are consistent with reports that PPIs are mostly weak inhibitors of cytochromes P450 in vivo. However, two members of the PPI class (esomeprazole and omeprazole) are more likely to serve as clinically relevant inhibitors of CYP2C19.


Assuntos
Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Esomeprazol/farmacologia , Fígado/efeitos dos fármacos , Omeprazol/farmacologia , Inibidores da Bomba de Prótons/farmacologia , 2-Piridinilmetilsulfinilbenzimidazóis/farmacologia , Hidrocarboneto de Aril Hidroxilases/metabolismo , Biotransformação , Células Cultivadas , Simulação por Computador , Citocromo P-450 CYP2C19 , Remoção de Radical Alquila , Dexlansoprazol , Diazepam/metabolismo , Relação Dose-Resposta a Droga , Interações de Medicamentos , Esomeprazol/farmacocinética , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Humanos , Cinética , Lansoprazol , Fígado/enzimologia , Microssomos Hepáticos/enzimologia , Modelos Biológicos , NADP/metabolismo , Omeprazol/farmacocinética , Pantoprazol , Inibidores da Bomba de Prótons/farmacocinética , Rabeprazol , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Especificidade por Substrato
8.
Xenobiotica ; 41(6): 476-85, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21381897

RESUMO

The purpose of this study was to assess the impact of interferon-α2b (IFN-α2b) on the expression of various drug-metabolizing enzymes and transporters in freshly prepared co-cultures (parenchymal and non-parenchymal cells) of human primary hepatocytes. At therapeutically relevant concentrations (from 1000 to 3000 IU/mL), IFN-α2b up-regulated STAT1 (signal transducer and activator of transcription factor 1) mRNA expression. Conversely, three cytochrome P450s (CYP1A2, CYP2B6, CYP2E1), a UDP-glucuronosyltransferase (UGT2B7), a sulphotransferase (SULT1A1) and organic anion transporter (OAT2) were significantly down-regulated (~50%; P < 0.05). Western blot analysis of CYP1A2, UGT2B7 and OAT2 protein supported the mRNA data. Two peroxisome proliferator activator receptor alpha (PPARα)-controlled genes (pyruvate dehydrogenase kinase 4 and adipose differentiation-related protein), CYP3A4 and multidrug resistance-associated protein 2 were significantly up-regulated (up to 223%; P < 0.05). On the other hand, SULT2A1, carboxylesterase 2, organic anion transporting peptide (OATP1B1, OATP1B3, OATP2B1), organic cation transporter 1, P-glycoprotein and breast cancer resistance protein mRNA expression was not significantly affected. Western blot analysis of CYP3A4 supported the mRNA data also. The present results demonstrated complex interactions between IFN-α2b and hepatocytes and the observed down-regulation of CYP1A2, OAT2 and UGT2B7 is consistent with reports of drug interactions between IFN-α2b and drugs such as theophylline, clozapine and gemfibrozil.


Assuntos
Antivirais/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Interferon-alfa/farmacologia , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Transporte Biológico/efeitos dos fármacos , Hidrolases de Éster Carboxílico/genética , Hidrolases de Éster Carboxílico/metabolismo , Células Cultivadas , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2B6 , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Família 2 do Citocromo P450 , Regulação para Baixo/efeitos dos fármacos , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Hepatócitos/enzimologia , Humanos , Interferon alfa-2 , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Desentoxicação Metabólica Fase I/genética , Desintoxicação Metabólica Fase II/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Oxirredutases N-Desmetilantes/genética , Oxirredutases N-Desmetilantes/metabolismo , Perilipina-2 , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , RNA Mensageiro/metabolismo , Proteínas Recombinantes , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Sulfotransferases/genética , Sulfotransferases/metabolismo , Regulação para Cima/efeitos dos fármacos
9.
Drug Metab Dispos ; 38(7): 1072-82, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20360302

RESUMO

17alpha-Ethinylestradiol (EE2), a component of oral contraceptives, is known to undergo considerable first-pass 3-O-sulfation in the intestine and liver. Once formed, the 3-O-sulfate conjugate (EE2-Sul) is detected in circulation at appreciable levels (versus parent EE2) and is present in bile. Therefore, hepatic uptake of EE2-Sul was assessed with suspensions of cryopreserved human primary hepatocytes. In this instance, there was evidence for active (temperature-dependent) uptake, which was described by a two-K(m) (Michaelis constant) model (K(m1) = 220 nM; K(m2) = 15.5 microM). Uptake was inhibited (approximately 90%) by bromosulfophthalein but not by tetraethylammonium or p-aminohippurate. In agreement, EE2-Sul was shown to be a substrate of recombinant organic anion transporter peptides (OATP1B1 and OATP2B1), and Na(+)/taurocholate-cotransporting polypeptide (NTCP), expressed individually in human embryonic kidney (HEK) 293 cells. Transport by OATP1B1 was described by two K(m) values (87 nM and 141 microM), whereas OATP2B1- and NTCP-mediated uptake into HEK-293 cells conformed to single K(m) kinetics (10.7 and 2.6 microM, respectively). EE2-Sul was also assessed as an efflux transporter substrate using membrane vesicles expressing bile salt export pump, breast cancer resistance protein (BCRP), and individual forms of multidrug resistance-associated protein (MRP1, MRP2, and MRP3). Transport studies were also conducted with a cell line expression P-glycoprotein. Only vesicles that contained BCRP exhibited ATP-dependent uptake of EE2-Sul (K(m1) = 2.9 and K(m2) = 307 microM). Collectively, the data show that hepatic uptake of EE2-Sul can be mediated by three transporters (OATP1B1, OATP2B1, and NTCP), whereas biliary excretion of EE2-Sul into bile likely involves BCRP.


Assuntos
Transporte Biológico Ativo/efeitos dos fármacos , Proteínas de Transporte/biossíntese , Etinilestradiol/análogos & derivados , Hepatócitos/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/biossíntese , Transportadores de Cassetes de Ligação de ATP/genética , Transporte Biológico Ativo/genética , Proteínas de Transporte/genética , Linhagem Celular Transformada , Etinilestradiol/metabolismo , Humanos , Cinética , Fígado/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado , Proteínas Associadas à Resistência a Múltiplos Medicamentos/biossíntese , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Transportadores de Ânions Orgânicos/biossíntese , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/biossíntese , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Simportadores/biossíntese , Simportadores/genética , Transfecção/métodos
10.
Drug Metab Dispos ; 38(7): 1064-71, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20360303

RESUMO

17alpha-Ethinylestradiol (EE2), a synthetic and potent estrogen receptor agonist, is extensively metabolized in both intestine and liver and is largely excreted in bile and urine as the 3-O-sulfate (EE2-Sul) and 3-O-glucuronide. In the present study, EE2-Sul was evaluated as a substrate of various transporters known to be expressed in the kidney. Uptake studies were performed with human epithelial cells [human embryonic kidney (HEK)-293] that contained individually expressed organic cation transporter 2 (OCT2), organic anion transporter (OAT) forms 3 and 4, and multidrug and toxin extrusion 1 (MATE1). The transporter phenotyping studies were extended to include insect cell (Sf9) membrane vesicles that expressed multidrug resistance-associated protein 4 (MRP4) and Madin-Darby canine kidney cells that expressed OAT1. Based on the results obtained, we concluded that EE2-Sul serves as a substrate of OAT3 and OAT4, but not OCT2, OAT1, MATE1, and MRP4. First, EE2-Sul uptake was highly increased in OAT3/HEK-293 cells (versus mock/HEK-293 cells) and was inhibited by OAT3 inhibitors such as bromosulfophthalein (BSP), cimetidine, and probenecid. OAT3-mediated uptake also conformed to single-K(m) (Michaelis constant) kinetics (K(m) = 21.1 microM). Second, EE2-Sul uptake was also significantly higher in OAT4/HEK-293 cells and was inhibited by BSP, methotrexate, and probenecid. In contrast to OAT3, OAT4-dependent uptake was characterized by a two-K(m) model (K(m1) = 1.6 microM; K(m2) = 195 microM). Based on the results of this study, we hypothesize that EE2-Sul is taken up into renal proximal tubule cells by OAT3, and OAT4 plays a role in its secretion into the renal brush border lumen.


Assuntos
Transporte Biológico/efeitos dos fármacos , Proteínas de Transporte/biossíntese , Etinilestradiol/análogos & derivados , Rim/metabolismo , Animais , Transporte Biológico/genética , Proteínas de Transporte/genética , Linhagem Celular Transformada , Cães , Etinilestradiol/metabolismo , Humanos , Insetos , Cinética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/biossíntese , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteína 1 Transportadora de Ânions Orgânicos/biossíntese , Proteína 1 Transportadora de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Transportadores de Ânions Orgânicos Sódio-Independentes/biossíntese , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Proteínas de Transporte de Cátions Orgânicos/biossíntese , Proteínas de Transporte de Cátions Orgânicos/genética , Transportador 2 de Cátion Orgânico , Especificidade por Substrato , Transfecção/métodos
11.
Mol Cancer Ther ; 8(12): 3341-9, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19996272

RESUMO

BMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases (Ki, <2 nmol/L). It is currently in phase I development for the treatment of a variety of human cancers. BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines (IC50, 5-365 nmol/L); the compound caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of the sub-G1 fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active in vivo in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a minimum effective dose of as low as 6.25 mg/kg dosed orally daily. Combination studies with BMS-754807 have been done on multiple human tumor cell types and showed in vitro synergies (combination index, <1.0) when combined with cytotoxic, hormonal, and targeted agents. The combination of cetuximab and BMS-754807 in vivo, at multiple dose levels, resulted in improved clinical outcome over single agent treatment. These data show that BMS-754807 is an efficacious, orally active growth factor 1 receptor/insulin receptor family-targeted kinase inhibitor that may act in combination with a wide array of established anticancer agents.


Assuntos
Pirazóis/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor de Insulina/antagonistas & inibidores , Triazinas/farmacologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Western Blotting , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cetuximab , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Poli(ADP-Ribose) Polimerases/metabolismo , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Triazinas/administração & dosagem , Triazinas/farmacocinética , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Med Chem ; 52(23): 7360-3, 2009 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-19778024
13.
J Pharmacol Exp Ther ; 330(3): 956-63, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19491323

RESUMO

The novel tyrosine kinase inhibitor dasatinib (Sprycel; BMS-354825) is approved for use in imatinib (Gleevec; STI 571)-resistant or -intolerant chronic myelogenous leukemia and may be useful for other tumors in the central nervous system (CNS). The objective of this study was to investigate the role of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in modulating the CNS penetration of dasatinib. Results from the in vitro studies indicate that cellular delivery of dasatinib is significantly limited by active efflux due to both P-gp and BCRP. Permeability studies indicated greater permeability in the basolateral-to-apical direction than in the apical-to-basolateral direction due to active efflux by P-gp or BCRP. Selective inhibitors of P-gp and BCRP, such as (R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo-(a,e)cyclopropa(c) cycloheptan-6-yl)-alpha-((5-quinoloyloxy)methyl)-1-piperazineethanol, trihydrochloride (zosuquidar; LY335979) and 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12alpha-octahydropyrazino1',2': 1,6pryrido3,4-bindol-3-yl)-propionic acid tert-butyl ester (Ko143), were able to restore the intracellular accumulation and abolish the directionality in net flux of dasatinib. In vivo brain distribution studies showed that the CNS distribution of dasatinib is limited, with the brain-to-plasma concentration ratios less than 0.12 in wild-type mice, which increased approximately 8-fold in Mdr1a/b(-/-) Bcrp1(-/-) mice. Dasatinib brain distribution was significantly increased in Mdr1a/b(-/-) mice and when wild-type mice were pretreated with LY335979. Simultaneous inhibition of P-gp and BCRP by elacridar [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide] (GF120918) resulted in a 5-fold increase in brain concentration. These in vitro and in vivo studies demonstrate that dasatinib is a substrate for the important efflux transporters p-glycoprotein and BCRP. These transport systems play a significant role in limiting the CNS delivery of dasatinib and may have direct implications in the treatment of primary and metastatic brain tumors.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Encéfalo/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Tiazóis/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Acridinas/farmacocinética , Animais , Antineoplásicos Fitogênicos/farmacocinética , Barreira Hematoencefálica , Linhagem Celular , Permeabilidade da Membrana Celular , Dasatinibe , Dibenzocicloeptenos/farmacologia , Cães , Resistencia a Medicamentos Antineoplásicos , Indicadores e Reagentes , Espectrometria de Massas , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Quinolinas/farmacologia , Tetra-Hidroisoquinolinas/farmacocinética , Vimblastina/farmacocinética
14.
Drug Metab Dispos ; 37(8): 1667-75, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19454483

RESUMO

17alpha-Ethinyl estradiol (EE) was systematically evaluated as a reversible and time-dependent inhibitor of 11 human drug-metabolizing cytochromes P450 (P450s) (CYP1A1, CYP1A2, CYP1B1, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2J2, CYP3A4, and CYP3A5) in vitro. When ranked, the lowest IC(50) (concentration of inhibitor required to decrease activity by 50%) values were obtained with recombinant CYP1A1 (rCYP1A1) [IC(50(total)) = IC(50(free)) = 2.7 microM] and CYP2C19 activity in human liver microsomes (HLM) [IC(50(total)) = 4.4 microM; IC(50(free)) = 2.8 microM]. For rCYP1A1, formal inhibition studies revealed that EE was a competitive inhibitor [K(i(free)) = 1.4 microM]. All the other IC(50) values were greater than 8.0 microM, and the weakest inhibition was observed with CYP1A2 activity in HLM (IC(50(free)) > 39 microM). In agreement, the IC(50) characterizing the inhibition of melatonin (MEL) 6-hydroxylation in human intestine microsomes (CYP1A1-catalyzed) was lower than that of HLM (0.91 versus >40 microM). Because EE is known to affect the pharmacokinetics of CYP2C19 probe drugs, this result raises the possibility that the concentration of EE during first pass may exceed 1000 nM, sufficient to affect CYP1A1 and CYP2C19, with less impact on CYP3A4 and other P450s. The results implicate intestinal CYP1A1, and possibly CYP2C19, as the loci of EE drug interactions with highly extracted drugs like MEL. Overall, it is very difficult to rationalize drug interactions involving EE based on direct inhibition of CYP2B6 (e.g., selegiline) and hepatic CYP1A2 (e.g., MEL, tizanidine, caffeine, and theophylline).


Assuntos
Anticoncepcionais Orais/farmacologia , Inibidores das Enzimas do Citocromo P-450 , Inibidores Enzimáticos/farmacologia , Etinilestradiol/farmacologia , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Hidrocarboneto de Aril Hidroxilases/metabolismo , Citocromo P-450 CYP1A1/antagonistas & inibidores , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Inibidores do Citocromo P-450 CYP1A2 , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP2C19 , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Interações de Medicamentos , Humanos , Hidroxilação , Técnicas In Vitro , Intestinos/efeitos dos fármacos , Intestinos/enzimologia , Cinética , Melatonina/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Oxirredutases N-Desmetilantes/antagonistas & inibidores , Oxirredutases N-Desmetilantes/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo
15.
J Pharm Biomed Anal ; 47(2): 351-9, 2008 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-18295429

RESUMO

A sensitive and specific liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) method was developed and validated for the determination of indocyanine green (ICG) in dog plasma and bile. An ICG analog (IR-820) was used as an internal standard. A protein precipitation method was used with acetonitrile for plasma sample preparation, whereas bile samples were diluted with water (120-fold) prior to analysis. Using MS/MS in the multiple reaction monitoring mode, ICG and IR-820 were detected in both matrices without interference. The lower limit of quantitation for ICG in dog plasma was 3 ng/mL, with an intra- and inter-day accuracy (%Bias) and precision (%CV) of less than 15%, so it was possible to study the pharmacokinetics of ICG in bile duct-cannulated dogs and assess their liver function after surgery. The method described herein is sensitive, selective and faster than other existing methods (e.g., spectrophotometry, HPLC/UV-vis detection, or HPLC/fluorescence detection).


Assuntos
Ânions/análise , Bile/química , Cromatografia Líquida/métodos , Corantes/análise , Verde de Indocianina/análise , Espectrometria de Massas em Tandem/métodos , Animais , Ânions/sangue , Bile/metabolismo , Corantes/química , Corantes/farmacocinética , Cães , Verde de Indocianina/química , Verde de Indocianina/farmacocinética , Estrutura Molecular , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
17.
Pharm Res ; 19(11): 1606-10, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12458665

RESUMO

PURPOSE: The in vivo hepatic extraction ratio of cynomolgus monkeys was correlated with the corresponding in vitro extraction ratios that were determined in monkey microsomal incubations. METHOD: For compounds that are eliminated mainly through liver phase I metabolism, the extraction ratio calculated from liver microsomal stability studies should correlate with their in vivo hepatic extraction ratios and also with their oral bioavailability in monkey. We used both well-stirred and parallel tube models of intrinsic clearance for the correlation. We also calculated extraction ratios for compounds within a given therapeutic area from fraction absorbed values that were estimated from the Caco-2 absorption model. RESULT: The present data show that in vitro extraction ratios in monkey microsomes are predictive of the in vivo hepatic extraction ratios in monkeys. All compounds with high extraction ratio (>70%) in vivo were successfully classified as high-extraction-ratio compounds based on the in vitro monkey microsomal stability data. From the results of this study, it appears that the parallel tube model provided a slightly better classification than the well-stirred model. CONCULUSIONS: The present method appears to be a valuable tool to rapidly screen and prioritize compounds with respect to liver first-pass metabolism in monkeys at an early phase of drug discovery.


Assuntos
Microssomos Hepáticos/metabolismo , Preparações Farmacêuticas/metabolismo , Tecnologia Farmacêutica/métodos , Animais , Células CACO-2 , Estabilidade Enzimática/efeitos dos fármacos , Estabilidade Enzimática/fisiologia , Previsões , Humanos , Macaca fascicularis , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , Microssomos Hepáticos/efeitos dos fármacos
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