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1.
Nat Nanotechnol ; 16(7): 820-829, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33795849

RESUMO

The poor transport of molecular and nanoscale agents through the blood-brain barrier together with tumour heterogeneity contribute to the dismal prognosis in patients with glioblastoma multiforme. Here, a biodegradable implant (µMESH) is engineered in the form of a micrometre-sized poly(lactic-co-glycolic acid) mesh laid over a water-soluble poly(vinyl alcohol) layer. Upon poly(vinyl alcohol) dissolution, the flexible poly(lactic-co-glycolic acid) mesh conforms to the resected tumour cavity as docetaxel-loaded nanomedicines and diclofenac molecules are continuously and directly released into the adjacent tumour bed. In orthotopic brain cancer models, generated with a conventional, reference cell line and patient-derived cells, a single µMESH application, carrying 0.75 mg kg-1 of docetaxel and diclofenac, abrogates disease recurrence up to eight months after tumour resection, with no appreciable adverse effects. Without tumour resection, the µMESH increases the median overall survival (∼30 d) as compared with the one-time intracranial deposition of docetaxel-loaded nanomedicines (15 d) or 10 cycles of systemically administered temozolomide (12 d). The µMESH modular structure, for the independent coloading of different molecules and nanomedicines, together with its mechanical flexibility, can be exploited to treat a variety of cancers, realizing patient-specific dosing and interventions.


Assuntos
Implantes Absorvíveis , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Encefálicas/tratamento farmacológico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular , Diclofenaco/farmacocinética , Diclofenaco/farmacologia , Docetaxel/farmacocinética , Docetaxel/farmacologia , Implantes de Medicamento/farmacocinética , Implantes de Medicamento/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Mol Pharm ; 18(4): 1792-1805, 2021 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-33739838

RESUMO

Human liver microsomes (HLM) and human hepatocytes (HH) are important in vitro systems for studies of intrinsic drug clearance (CLint) in the liver. However, the CLint values are often in disagreement for these two systems. Here, we investigated these differences in a side-by-side comparison of drug metabolism in HLM and HH prepared from 15 matched donors. Protein expression and intracellular unbound drug concentration (Kpuu) effects on the CLint were investigated for five prototypical probe substrates (bupropion-CYP2B6, diclofenac-CYP2C9, omeprazole-CYP2C19, bufuralol-CYP2D6, and midazolam-CYP3A4). The samples were donor-matched to compensate for inter-individual variability but still showed systematic differences in CLint. Global proteomics analysis outlined differences in HLM from HH and homogenates of human liver (HL), indicating variable enrichment of ER-localized cytochrome P450 (CYP) enzymes in the HLM preparation. This suggests that the HLM may not equally and accurately capture metabolic capacity for all CYPs. Scaling CLint with CYP amounts and Kpuu could only partly explain the discordance in absolute values of CLint for the five substrates. Nevertheless, scaling with CYP amounts improved the agreement in rank order for the majority of the substrates. Other factors, such as contribution of additional enzymes and variability in the proportions of active and inactive CYP enzymes in HLM and HH, may have to be considered to avoid the use of empirical scaling factors for prediction of drug metabolism.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Hepatócitos/enzimologia , Fígado/enzimologia , Microssomos Hepáticos/enzimologia , Bupropiona/farmacocinética , Sistema Enzimático do Citocromo P-450/análise , Diclofenaco/farmacocinética , Etanolaminas/farmacocinética , Eliminação Hepatobiliar , Humanos , Fígado/citologia , Midazolam/farmacocinética , Omeprazol/farmacocinética , Proteoma/análise , Proteômica
3.
Int Immunopharmacol ; 86: 106723, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32615451

RESUMO

Diclofenac (DCF) is a widely used nonsteroidal anti-inflammatory drug, but it comes with a high risk of drug-induced liver injury (DILI). Despite the quinone-imine adduct pathways, the immunotoxicity is recently considered as another factor for DILI. However, such immune responses are still elusive. In the present study, investigation of the immune response in the acute hepatotoxicity model of TgCYP3A4/hPXR-humanized mice was conducted by administration of DCF and DCF metabolites, respectively. In a single dose intraperitoneal injection of 80 mg/kg DCF, the pharmacokinetic results showed the major DCF metabolites, including 4'-hydroxy-diclofenac (4'-OH-DCF), 5-hydroxy-diclofenac (5-OH-DCF) and diclofenac glucuronide (DCF-G) were generated after DCF treatment. Not only DCF, but those DCF metabolites could also directly cause different degrees of acute liver injury as significantly increased the serum ALT levels in a short time period in the TgCYP3A4/hPXR-humanized mice. Furthermore, the three DCF metabolites could directly stimulate the significant elevation of serum immune-related factors in varying degrees. Transcriptome analysis revealed the differentially expressed genes in the liver of DCF-G treated mice were mostly involved with the "immune system process" and "cell death" and related to "IL-17 signaling pathway" and "TNF-α signaling pathway", but 5-OH-DCF had little effect on the expressions of those genes. These results indicate that the metabolite DCF-G plays an important role in the activation of the hepatic immune system, which might be involved in the pathogenesis of DCF-induced acute liver injury.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Diclofenaco/efeitos adversos , Diclofenaco/farmacocinética , Fígado/imunologia , Fígado/metabolismo , Alanina Transaminase/sangue , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacocinética , Morte Celular/efeitos dos fármacos , Citocinas/sangue , Diclofenaco/administração & dosagem , Diclofenaco/análogos & derivados , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Glucuronídeos/administração & dosagem , Glucuronídeos/efeitos adversos , Glucuronídeos/farmacocinética , Humanos , Imunidade/efeitos dos fármacos , Injeções Intraperitoneais , Interleucina-17/genética , Fígado/lesões , Fígado/patologia , Camundongos Transgênicos , Mapas de Interação de Proteínas , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/efeitos dos fármacos
4.
Xenobiotica ; 50(11): 1332-1340, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32432967

RESUMO

Diclofenac is an extensively used nonsteroidal anti-inflammatory drug, but gastrointestinal liabilities and cardiovascular complications take the shine away from such a widely prescribed drug. On the other hand, rutin, a dietary bioflavonoid, has quite a few pharmacological attributes to improve the efficacy and reduce the dose-related toxicities of diclofenac through the intended food-drug/herb-drug interaction. The aim of the present research work was to investigate the role of rutin on pharmacokinetic modulation and the consequent efficacy of diclofenac. At first, pharmacodynamics and pharmacokinetics of diclofenac as alone and in the presence of rutin were investigated orally in a rat model. Then, mechanistic studies were performed to explain the effect of rutin on improvement in oral exposure as well as the efficacy of diclofenac using a battery of in-vitro/in-situ/in-vivo studies. Results displayed that rutin enhanced efficacy as well as oral bioavailability of diclofenac in rats. A marked increase in permeability of diclofenac by rutin was displayed that is linked to inhibition of Breast Cancer Resistance Protein (BCRP) transporters. There was no significant effect of rutin on the modulation of intestinal transit, CYP2C9 inhibition in human liver microsomes, and CYP2C9/CYP2C11 expression in rat liver tissues to boost the oral exposure of diclofenac. Rutin is found to be an inhibitor for BCRP transporters and can act as an oral bioavailability enhancer for a drug like diclofenac.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Diclofenaco/farmacocinética , Rutina/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Animais , Interações Medicamentosas , Ratos
5.
Mater Sci Eng C Mater Biol Appl ; 108: 110385, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31923967

RESUMO

The growing interest in the use of polysaccharides nanoparticles for biomedical applications is related to the recent progresses on the synthesis of cellulose-based polymers with the specific functionalities. In particular, cellulose graft copolymers are emerging as amphiphilic materials suitable to fabricate smart nanoparticles for drug delivery applications. In this work, a cellulose-graft-poly(ε-caprolactone) (cell-g-PCL) was synthetized and characterized by FTIR, TGA and DSC in order to validate the synthesis process. We demonstrated that fast evaporation processes promoted cell-g-PCL self-assembly to form nanomicellar structures with hydrodynamic radius ranged from 30 to 60 nm as confirmed by TEM analysis. Moreover, the application of controlled electrostatic forces on solvent evaporation - namely electrospraying - allowed generating round-like nanoscaled particles, as confirmed by SEM supported via image analysis. We demonstrated also that sodium diclofenac (DS) drastically influenced the mechanism of particle formation, favoring the deposition of erythrocyte-like particles with highly concave surfaces, not penalizing the encapsulation efficiency of nanoparticles (>80%). The release profile showed a fast delivery of DS - about 60% during the first 24 h - followed by a sustained release - about 20% during the next 6 days - strictly related to the peculiar weak interactions among amphiphilic polymer segments and water molecules, thus suggesting a successful use of electrosprayed cell-g-PCL nanoparticles for therapeutic treatments in nanomedicine.


Assuntos
Celulose/química , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Poliésteres/química , Diclofenaco/química , Diclofenaco/farmacocinética , Liberação Controlada de Fármacos , Humanos , Espectroscopia de Ressonância Magnética , Células-Tronco Mesenquimais/efeitos dos fármacos , Nanopartículas/toxicidade , Nanotecnologia/métodos , Polímeros/síntese química , Polímeros/química , Propanóis/química , Solventes/química , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria
6.
Biomacromolecules ; 21(1): 152-162, 2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31502452

RESUMO

Polyelectrolyte complexation, the combination of anionically and cationically charged polymers through ionic interactions, can be used to form hydrogel networks. These networks can be used to encapsulate and release cargo, but the release of cargo is typically rapid, occurring over a period of hours to a few days and they often exhibit weak, fluid-like mechanical properties. Here we report the preparation and study of polyelectrolyte complexes (PECs) from sodium hyaluronate (HA) and poly[tris(hydroxypropyl)(4-vinylbenzyl)phosphonium chloride], poly[triphenyl(4-vinylbenzyl)phosphonium chloride], poly[tri(n-butyl)(4-vinylbenzyl)phosphonium chloride], or poly[triethyl(4-vinylbenzyl)phosphonium chloride]. The networks were compacted by ultracentrifugation, then their composition, swelling, rheological, and self-healing properties were studied. Their properties depended on the structure of the phosphonium polymer and the salt concentration, but in general, they exhibited predominantly gel-like behavior with relaxation times greater than 40 s and self-healing over 2-18 h. Anionic molecules, including fluorescein, diclofenac, and adenosine-5'-triphosphate, were encapsulated into the PECs with high loading capacities of up to 16 wt %. Fluorescein and diclofenac were slowly released over 60 days, which was attributed to a combination of hydrophobic and ionic interactions with the dense PEC network. The cytotoxicities of the polymers and their corresponding networks with HA to C2C12 mouse myoblast cells was investigated and found to depend on the structure of the polymer and the properties of the network. Overall, this work demonstrates the utility of polyphosphonium-HA networks for the loading and slow release of ionic drugs and that their physical and biological properties can be readily tuned according to the structure of the phosphonium polymer.


Assuntos
Compostos Organofosforados/química , Polieletrólitos/química , Polieletrólitos/farmacocinética , Trifosfato de Adenosina/química , Trifosfato de Adenosina/farmacocinética , Animais , Linhagem Celular , Diclofenaco/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Fluoresceína/química , Fluoresceína/farmacocinética , Ácido Hialurônico/química , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Microscopia Eletrônica de Varredura , Mioblastos/efeitos dos fármacos , Polieletrólitos/toxicidade , Polímeros/síntese química , Reologia , Testes de Toxicidade , Ultracentrifugação
7.
Retina ; 40(9): 1838-1845, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31800462

RESUMO

PURPOSE: To evaluate the vitreous concentration of different nonsteroidal anti-inflammatory drugs (NSAIDs) after topical administration and the related prostaglandin E2 (PGE2) levels in patients undergoing pars plana vitrectomy. METHODS: A prospective, randomized, investigator-masked study was performed. One hundred four patients scheduled for a pars plana vitrectomy for an epiretinal membrane or a macular hole were randomized to receive topical diclofenac 0.1%, indomethacin 0.5%, nepafenac 0.3%, bromfenac 0.09%, or placebo 3 days before surgery. At the beginning of surgery, a sample of undiluted vitreous was collected in each patient to assess NSAIDs concentration and PGE2 levels. RESULTS: The median vitreous concentrations were 203.35 (interquartile range 146.54-264.18) pg/mL for diclofenac, 243.45 (interquartile range 156.96-365.37) pg/mL for nepafenac, 438.21 pg/mL (interquartile range, 282.52-645.87) for its active metabolite amfenac, 350.14 (interquartile range, 290.88-481.95) pg/mL for indomethacin, and 274.59 (245.43-358.25) pg/mL for bromfenac. Vitreous PGE2 levels were significantly lower for all the NSAIDs groups compared with the control group (P < 0.001). A statistically significant higher vitreous PGE2 level was found in the diclofenac group compared with the other NSAIDs groups (P < 0.05). CONCLUSION: Topical NSAIDs achieve sufficient vitreous concentration to decrease vitreous PGE2 levels compared with the control group. The different efficacy in reducing PGE2 concentration may affect the management of posterior segment inflammation.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Dinoprostona/metabolismo , Corpo Vítreo/metabolismo , Administração Oftálmica , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/farmacocinética , Benzenoacetamidas/administração & dosagem , Benzenoacetamidas/farmacocinética , Benzofenonas/administração & dosagem , Benzofenonas/farmacocinética , Bromobenzenos/administração & dosagem , Bromobenzenos/farmacocinética , Cromatografia Líquida de Alta Pressão , Diclofenaco/administração & dosagem , Diclofenaco/farmacocinética , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática , Membrana Epirretiniana/metabolismo , Membrana Epirretiniana/cirurgia , Feminino , Humanos , Indometacina/administração & dosagem , Indometacina/farmacocinética , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas , Fenilacetatos/administração & dosagem , Fenilacetatos/farmacocinética , Estudos Prospectivos , Perfurações Retinianas/metabolismo , Perfurações Retinianas/cirurgia , Vitrectomia
8.
Nutrients ; 11(10)2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618937

RESUMO

Adlay (Coix lachryma-jobi L. var. ma-yuen Stapf) contains various phytonutrients for treating many diseases in Asia. To investigate whether orally administered adlay bran oil (ABO) can cause drug interactions, the effects of ABO on the pharmacokinetics of five cytochrome P450 (CYP) probe drugs were evaluated. Rats were given a single oral dose (2.5 mL/kg BW) of ABO 1 h before administration of a drug cocktail either orally or intravenously, and blood was collected at various time points. A single oral dose of ABO administration did not affect the pharmacokinetics of five probe drugs when given as a drug cocktail intravenously. However, ABO increased plasma theophylline (+28.4%), dextromethorphan (+48.7%), and diltiazem (+46.7%) when co-administered an oral drug cocktail. After 7 days of feeding with an ABO-containing diet, plasma concentrations of theophylline (+45.4%) and chlorzoxazone (+53.6%) were increased after the oral administration of the drug cocktail. The major CYP enzyme activities in the liver and intestinal tract were not affected by ABO treatment. Results from this study indicate that a single oral dose or short-term administration of ABO may increase plasma drug concentrations when ABO is given concomitantly with drugs. ABO is likely to enhance intestinal drug absorption. Therefore, caution is needed to avoid food-drug interactions between ABO and co-administered drugs.


Assuntos
Capsaicina/química , Clorzoxazona/farmacocinética , Dextrometorfano/farmacocinética , Diclofenaco/farmacocinética , Diltiazem/farmacocinética , Interações Alimento-Droga , Óleos de Plantas/administração & dosagem , Teofilina/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Clorzoxazona/administração & dosagem , Clorzoxazona/toxicidade , Sistema Enzimático do Citocromo P-450/metabolismo , Dextrometorfano/administração & dosagem , Dextrometorfano/toxicidade , Diclofenaco/administração & dosagem , Diclofenaco/toxicidade , Diltiazem/administração & dosagem , Diltiazem/toxicidade , Absorção Intestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Intestinos/enzimologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Óleos de Plantas/isolamento & purificação , Óleos de Plantas/toxicidade , Ratos Sprague-Dawley , Medição de Risco , Teofilina/administração & dosagem , Teofilina/toxicidade
9.
Drug Metab Dispos ; 47(10): 1080-1092, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31399506

RESUMO

In the present work, in vivo transporter knockout (KO) mouse models were used to characterize the disposition of diclofenac (DCF) and its primary metabolites following a single subtoxic dose in mice lacking breast cancer resistance protein (Bcrp) or multidrug resistance-associated protein (Mrp)3. The results indicate that Bcrp acts as a canalicular efflux mediator for DCF, as wild-type (WT) mice had biliary excretion values that were 2.2- to 2.6-fold greater than Bcrp KO mice, although DCF plasma levels were not affected. The loss of Bcrp resulted in a 1.8- to 3.2-fold increase of diclofenac acyl glucuronide (DCF-AG) plasma concentrations in KO animals compared with WT mice, while the biliary excretion of DCF-AG increased 1.4-fold in WT versus KO mice. Furthermore, Mrp3 was found to mediate the basolateral transport of DCF-AG, but not DCF or 4'-hydroxy diclofenac. WT mice had DCF-AG plasma concentrations 7.0- to 8.6-fold higher than Mrp3 KO animals; however, there were no changes in biliary excretion of DCF-AG. Vesicular transport experiments with human MRP3 demonstrated that MRP3 is able to transport DCF-AG via low- and high-affinity binding sites. The low-affinity MRP3 transport had a V max and K m of 170 pmol/min/mg and 98.2 µM, respectively, while the high-affinity V max and K m parameters were estimated to be 71.9 pmol/min/mg and 1.78 µM, respectively. In summary, we offer evidence that the disposition of DCF-AG can be affected by both Bcrp and Mrp3, and these findings may be applicable to humans.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Diclofenaco/análogos & derivados , Glucuronídeos/farmacocinética , 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 , Animais , Diclofenaco/farmacocinética , Diclofenaco/toxicidade , Glucuronídeos/toxicidade , Masculino , Camundongos , Camundongos Knockout , Distribuição Tecidual
10.
Drug Dev Res ; 80(7): 948-957, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31318064

RESUMO

Diclofenac is one of the world's largest selling nonsteroidal anti-inflammatory drugs. The major concerns related to oral diclofenac therapy are gastrointestinal and cardiovascular side effects for which explicitly emphasis has been given to use it at lowest effective dose for the shortest duration. On the other hand, IS01957 has been designed under the purview of anti-inflammatory drug and bioavailability enhancer. IS01957 have dual action on inflammation and nociception with acceptable safety profile. In the quest for a suitable combination with improved therapeutic efficacy and better tolerability, pharmacodynamic and pharmacokinetic interaction studies were performed for diclofenac with or without IS01957 in mice model. Results showed that IS01957 enhanced both anti-inflammatory effect and plasma concentration of diclofenac upon concomitant oral administration. These interesting results steered to enumerate the possible role of IS01957 towards diclofenac pharmacokinetics through a panel of mechanistic investigations: (a) BCRP dependent ATPase activity was markedly interfered by IS01957; (b) IS01957 increased the intestinal permeability of diclofenac in the single pass in-situ perfusion model; (c) IS01957 inhibited the CYP2C9 catalyzed diclofenac 4-hydroxylation in human liver microsomes. Immunoblotting results suggest that diclofenac action was improved significantly in the presence of IS01957 involving MAPK pathways. Finally acute gastric damage study showed that IS01957 in combination with diclofenac was better to improve the desired PGE2 level as compare to alone. In nutshell, IS01957 have potential to augment the efficacy of diclofenac through pharmacokinetic modulation. Further investigations are required for dose reduction of diclofenac to combat its liabilities before going into clinical setting.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Diclofenaco/farmacocinética , Morfolinas/farmacologia , Propionatos/farmacologia , Adenosina Trifosfatases/antagonistas & inibidores , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Citocromo P-450 CYP2C9/metabolismo , Diclofenaco/administração & dosagem , Dinoprostona/metabolismo , Interações Medicamentosas , Sinergismo Farmacológico , Feminino , Mucosa Gástrica/metabolismo , Hidroxilação/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Morfolinas/administração & dosagem , Permeabilidade/efeitos dos fármacos , Ratos
11.
Eur J Drug Metab Pharmacokinet ; 44(5): 681-689, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31077065

RESUMO

BACKGROUND: A 1-mL aqueous solution for parenteral injection containing diclofenac sodium and hydroxypropyl-ß-cyclodextrin, presently on the market for intramuscular and subcutaneous administration (Akis®/Dicloin®), was further developed for intravenous (i.v.) bolus administration. OBJECTIVES: The study objective was to compare the tolerability and diclofenac pharmacokinetics after a single i.v. bolus of the investigational solution to those of other parenteral diclofenac products. METHODS: The study comprised three parts: (i) Part 1: an exploratory dose-escalation study to evaluate the tolerability of 25 mg/1 mL, 50 mg/1 mL and 75 mg/1 mL diclofenac sodium formulations administered as a single 5-s i.v. bolus; (ii) Part 2: an exploratory, randomised, crossover study to evaluate the pharmacokinetics of diclofenac following 5-, 15-, and 30-s i.v. bolus injections of diclofenac sodium 75 mg/1 mL; (iii) Part 3: a randomised crossover study to compare the pharmacokinetics of diclofenac following a 5-s i.v. bolus of the 75 mg/1 mL solution to the pharmacokinetics of diclofenac following a 30-min i.v. infusion or intramuscular administration of a 75 mg/3 mL reference formulation. RESULTS: The extent of exposure to diclofenac sodium afforded by the 5-s i.v. bolus of 75 mg/1 mL was equivalent to that provided by the 30-min i.v. infusion of 75 mg/3 mL, since the 90% confidence interval of the geometric mean ratio (GMR) of the area under the curve (AUC) from time 0 to the last plasma concentration time t (AUC0-t) was within the limits 80.00-125.00%, as was the 90% confidence interval of the GMR of the AUC from time 0 extrapolated to infinity (AUC0-∞). The maximum observed plasma concentration (Cmax) was approximately 2.7-fold higher and was achieved earlier (0.05 vs. 0.50 h) with the 1 mL than with the 3 mL formulation, and was similar to data published for a 75 mg/2 mL formulation given as a 15-s i.v. bolus. CONCLUSIONS: Diclofenac sodium 75 mg/1 mL solution administered as a 5-s i.v. bolus was well tolerated. The pharmacokinetic profile, which showed a faster onset and a higher concentration peak than seen for other products and administration routes, suggests a superior analgesic effect.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacocinética , Diclofenaco/efeitos adversos , Diclofenaco/farmacocinética , 2-Hidroxipropil-beta-Ciclodextrina/administração & dosagem , 2-Hidroxipropil-beta-Ciclodextrina/efeitos adversos , 2-Hidroxipropil-beta-Ciclodextrina/farmacocinética , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/administração & dosagem , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Diclofenaco/administração & dosagem , Feminino , Humanos , Injeções Intramusculares , Injeções Intravenosas/métodos , Pessoa de Meia-Idade , Adulto Jovem
12.
Drug Deliv ; 26(1): 481-489, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30957571

RESUMO

OBJECTIVES: Ginsenosides Rb1 (Rb1) could form micelles in aqueous solutions. Self-assembled Rb1 micelles could potentially be utilized as ocular drug delivery system, and it was postulated that the encapsulation of a medicine within Rb1 micelles might strengthen the drug's therapeutic action and reduce side effects. METHODS: Diclofenac-loaded Rb1 micelles (Rb1-Dic micelles) were formulated, optimized, and then further evaluated for in vitro cytotoxicity/in vivo ocular irritation, in vivo corneal permeation, and in vivo anti-inflammatory efficacy. RESULTS: Rb1 self-assembled into micelles with ultra-small particle size (<8 nm) in a homogeneous distribution state (polydispersity index [PDI] < 0.3). Diclofenac was highly encapsulated into the micelles according to the weight ratios of Rb1 to diclofenac. The ophthalmic solution of Rb1-Dic micelle was simple to prepare. Rb1 had good cellular tolerance, and it also improved the cellular tolerance of the encapsulated diclofenac. Rb1-Dic micelles also showed non-irritants to the rabbit eyes. The use of Rb1 micelles significantly improved the in vivo corneal permeation as well as the anti-inflammatory efficacy of diclofenac when compared to commercial diclofenac eye drops. CONCLUSION: Rb1 micelle formulations have great potential as a novel ocular drug delivery system to improve the bioavailability of drugs such as diclofenac.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Córnea/metabolismo , Diclofenaco/administração & dosagem , Portadores de Fármacos/química , Ginsenosídeos/química , Nanopartículas/química , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/toxicidade , Disponibilidade Biológica , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diclofenaco/farmacocinética , Diclofenaco/toxicidade , Células Epiteliais/efeitos dos fármacos , Humanos , Micelas , Soluções Oftálmicas , Tamanho da Partícula , Coelhos , Solubilidade
13.
Molecules ; 23(6)2018 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-29914211

RESUMO

Honokiol (2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2-enyl-phenol) and magnolol (4-Allyl-2-(5-allyl-2-hydroxy-phenyl)phenol) are the major active polyphenol constituents of Magnolia officinalis (Magnoliaceae) bark, which has been widely used in traditional Chinese medicine (Houpu Tang) for the treatment of various diseases, including anxiety, stress, gastrointestinal disorders, infection, and asthma. The aim of this study was to investigate the direct effects of honokiol and magnolol on hepatic CYP1A and 2C-mediated metabolism in vitro using rat liver microsomes and in vivo using the Sprague-Dawley rat model. Honokiol and magnolol inhibited in vitro CYP1A activity (probe substrate: phenacetin) more potently than CYP2C activity (probe substrate: diclofenac): The mean IC50 values of honokiol for the metabolism of phenacetin and diclofenac were 8.59 µM and 44.7 µM, while those of magnolol were 19.0 µM and 47.3 µM, respectively. Notably, the systemic exposure (AUC and Cmax) of phenacetin, but not of diclofenac, was markedly enhanced by the concurrent administration of intravenous honokiol or magnolol. The differential effects of the two phytochemicals on phenacetin and diclofenac in vivo pharmacokinetics could at least be partly attributed to their lower IC50 values for the inhibition of phenacetin metabolism than for diclofenac metabolism. In addition, the systemic exposure, CL, and Vss of honokiol and magnolol tended to be similar between the rat groups receiving phenacetin and diclofenac. These findings improve our understanding of CYP-mediated drug interactions with M. officinalis and its active constituents.


Assuntos
Compostos de Bifenilo/administração & dosagem , Citocromo P-450 CYP1A1/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Diclofenaco/farmacocinética , Lignanas/administração & dosagem , Fígado/enzimologia , Fenacetina/farmacocinética , Administração Intravenosa , Animais , Compostos de Bifenilo/farmacologia , Cromatografia Líquida de Alta Pressão , Interações Medicamentosas , Regulação da Expressão Gênica/efeitos dos fármacos , Lignanas/farmacologia , Fígado/citologia , Microssomos Hepáticos/enzimologia , Estrutura Molecular , Ratos , Ratos Sprague-Dawley
14.
Int J Nanomedicine ; 13: 2395-2404, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29713169

RESUMO

BACKGROUND: Colon-specific pulsatile drug release, as a combined drug controlled-release model, is a useful drug delivery manner for a series of diseases. New nanomedicines and related preparation methods are highly desired. METHODS: With diclofenac sodium (DS) as a model drug, a new type of structural nanocomposite (SC), in which composite polyvinylpyrrolidone (PVP)-DS core was coated by shellac, was fabricated via modified coaxial electrospinning. For comparison, traditional PVP-DS monolithic hydrophilic nanocomposites (HCs) were generated using a traditional blending process. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), attenuated total reflectance-Fourier transform infrared (ATR-FTIR), water contact angle (WCA), and in vitro dissolution and ex vivo permeation tests were conducted to characterize the composites. RESULTS: SEM images demonstrated that both composites were linear nanofibers with smooth surface morphology and cross sections. TEM disclosed that the SCs had a thin shellac sheath layer of approximately 12 nm. XRD and ATR-FTIR results demonstrated that the crystalline DS was converted into amorphous composites with PVP because of favorable secondary interactions. WCA and in vitro dissolution tests demonstrated that the sheath shellac layers in SC could resist acid conditions and provide typical colon-specific pulsatile release, rather than a pulsatile release of HC under acid conditions. Ex vivo permeation results demonstrated that the SCs were able to furnish a tenfold drug permeation rate than the DS particles on the colon membrane. CONCLUSION: A new SC with a shellac coating on hydrophilic amorphous nanocomposites could furnish a colon-specific pulsatile drug release profile. The modified coaxial process can be exploited as a useful tool to create nanocoatings.


Assuntos
Colo/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Nanofibras/administração & dosagem , Nanotecnologia/métodos , Animais , Preparações de Ação Retardada/química , Diclofenaco/administração & dosagem , Diclofenaco/farmacocinética , Liberação Controlada de Fármacos , Interações Hidrofóbicas e Hidrofílicas , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Nanofibras/química , Povidona/química , Resinas Vegetais/química , Espectroscopia de Infravermelho com Transformada de Fourier , Sus scrofa , Difração de Raios X
15.
Eur J Clin Pharmacol ; 74(5): 601-609, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29368187

RESUMO

PURPOSE: The objective of this study is to assess the effects of green tea and its major catechin component, (-)-epigallocatechin gallate (EGCG), on CYP2C9-mediated substrate metabolism in vitro, and the pharmacokinetics of fluvastatin in healthy volunteers. METHODS: The metabolism of diclofenac and fluvastatin in human recombinant CYP2C9 was investigated in the presence of EGCG. In a randomized three-phase crossover study, 11 healthy volunteers ingested a single 20-mg dose of fluvastatin with green tea extract (GTE), containing 150 mg of EGCG, along with water (300 mL), brewed green tea (300 mL), or water (300 mL) after overnight fasting. Plasma concentrations of fluvastatin and EGCG were measured by ultra-performance liquid chromatography with fluorescence detection and a single mass spectrometer. RESULTS: EGCG inhibited diclofenac 4'-hydroxylation and fluvastatin degradation with IC50 of 2.23 and 48.04 µM, respectively. Brewed green tea used in the clinical study also dose-dependently inhibited the metabolism of diclofenac and fluvastatin in vitro. However, no significant effects of GTE and brewed green tea were observed in plasma concentrations of fluvastatin. The geometric mean ratios with 90% CI for area under the plasma concentration-time curve (AUC0-∞) of fluvastatin were 0.993 (0.963-1.024, vs. brewed green tea) and 0.977 (0.935-1.020, vs. GTE). CONCLUSIONS: Although in vitro studies indicated that EGCG and brewed green tea produce significant inhibitory effects on CYP2C9 activity, the concomitant administration of green tea and fluvastatin in healthy volunteers did not influence the pharmacokinetics of fluvastatin.


Assuntos
Catequina/análogos & derivados , Citocromo P-450 CYP2C9/metabolismo , Ácidos Graxos Monoinsaturados/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Indóis/farmacocinética , Chá , Adulto , Anti-Inflamatórios não Esteroides/farmacocinética , Catequina/análise , Catequina/sangue , Catequina/farmacocinética , Catequina/farmacologia , Estudos Cross-Over , Diclofenaco/farmacocinética , Ácidos Graxos Monoinsaturados/sangue , Feminino , Fluvastatina , Interações Alimento-Droga , Voluntários Saudáveis , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Indóis/sangue , Masculino , Chá/química , Adulto Jovem
16.
Clin Pharmacol Ther ; 104(1): 188-200, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29027194

RESUMO

The accuracy of physiologically based pharmacokinetic (PBPK) model prediction in children, especially those younger than 2 years old, has not been systematically evaluated. The aim of this study was to characterize the pediatric predictive performance of the PBPK approach for 10 drugs extensively metabolized by CYP1A2 (theophylline), CYP2C8 (desloratidine, montelukast), CYP2C9 (diclofenac), CYP2C19 (esomeprazole, lansoprazole), CYP2D6 (tramadol), and CYP3A4 (itraconazole, ondansetron, sufentanil). Model performance in children was evaluated by comparing simulated plasma concentration-time profiles with observed clinical results for each drug and age group. PBPK models reasonably predicted the pharmacokinetics of desloratadine, diclofenac, itraconazole, lansoprazole, montelukast, ondansetron, sufentanil, theophylline, and tramadol across all age groups. Collectively, 58 out of 67 predictions were within 2-fold and 43 out of 67 predictions within 1.5-fold of observed values. Developed PBPK models can reasonably predict exposure in children age 1 month and older for an array of predominantly CYP metabolized drugs.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Biológicos , Preparações Farmacêuticas/metabolismo , Farmacocinética , Acetatos/metabolismo , Acetatos/farmacocinética , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacocinética , Antiasmáticos/metabolismo , Antiasmáticos/farmacocinética , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacocinética , Antifúngicos/metabolismo , Antifúngicos/farmacocinética , Broncodilatadores/metabolismo , Broncodilatadores/farmacocinética , Criança , Pré-Escolar , Ciclopropanos , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Diclofenaco/metabolismo , Diclofenaco/farmacocinética , Esomeprazol/metabolismo , Esomeprazol/farmacocinética , Antagonistas não Sedativos dos Receptores H1 da Histamina/metabolismo , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacocinética , Humanos , Lactente , Recém-Nascido , Itraconazol/metabolismo , Itraconazol/farmacocinética , Lansoprazol/metabolismo , Lansoprazol/farmacocinética , Loratadina/análogos & derivados , Loratadina/metabolismo , Loratadina/farmacocinética , Ondansetron/metabolismo , Ondansetron/farmacocinética , Inibidores da Bomba de Prótons/metabolismo , Inibidores da Bomba de Prótons/farmacocinética , Quinolinas/metabolismo , Quinolinas/farmacocinética , Antagonistas da Serotonina/metabolismo , Antagonistas da Serotonina/farmacocinética , Sufentanil/metabolismo , Sufentanil/farmacocinética , Sulfetos , Teofilina/metabolismo , Teofilina/farmacocinética
17.
Colloids Surf B Biointerfaces ; 162: 8-15, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29132043

RESUMO

The poor ability of many drugs to cross skin layers is the main limiting factor for the exploitation of the transdermal route for drug delivery. As a consequence, several approaches have been proposed to overcome the skin barrier, such as the inclusion of penetration enhancers in the topically applied drug solutions and emulsions. In this work, the penetration enhancer diethylene glycol monoethyl ether was included in novel diclofenac acid nanocrystal formulations, developed using the wet media milling technique and Poloxamer 188 as stabilizer. The nanosuspensions were characterized by different techniques such as scanning electron microscopy, differential scanning calorimetry, X-ray powder diffractometry, Fourier-transform infrared spectroscopy and photon correlation spectroscopy. The influence of diethylene glycol monoethyl ether on (trans)dermal delivery of diclofenac nanosuspensions was evaluated by in vitro studies using Franz diffusion cells and pig skin. RESULTS: demonstrated that the presence of diethylene glycol monoethyl ether influences the Poloxamer 188 ability to stabilize the nanocrystals during the milling process, leading to larger particles as compared to penetration enhancer-free nanosuspensions. As previously reported, the in vitro permeation studies indicate the nanosizing as a key factor in the dermal penetration of topically applied diclofenac. Surprisingly enough, the inclusion of increasing amounts of the penetration enhancer in the formulation decreased the diclofenac accumulation in the stratum corneum, while showing no significant effect on the drug delivered to the epidermis. Overall, the present results exclude a synergistic effect of the nanosizing approach and the addition of diethylene glycol monoethyl ether in regard to the skin penetration of diclofenac applied as a nanosuspension.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Diclofenaco/farmacocinética , Etilenoglicóis/farmacologia , Excipientes/farmacologia , Nanopartículas/química , Pele/metabolismo , Administração Cutânea , Animais , Cultura em Câmaras de Difusão , Nanopartículas/ultraestrutura , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Poloxâmero/química , Pele/efeitos dos fármacos , Absorção Cutânea/efeitos dos fármacos , Suínos , Técnicas de Cultura de Tecidos
18.
Arch Toxicol ; 91(11): 3543-3550, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28500425

RESUMO

4-tert-Octylphenol (4-tOP) is an endocrine-disrupting chemical. It is mainly metabolized into glucuronide by UDP-glucuronosyltransferase (UGT) enzymes in humans. The purpose of this study was to assess inter-individual variability in and the possible roles of UGT isoforms in hepatic 4-tOP glucuronidation in the humans. 4-tOP glucuronidation activities in the liver microsomes and recombinant UGTs of humans were assessed at broad substrate concentrations, and kinetics were analyzed. Correlation analyses between 4-tOP and diclofenac or 4-hydroxybiphenyl activities in pooled and individual human liver microsomes were also performed. Typical CLint values were 17.8 mL/min/mg protein for the low type, 25.2 mL/min/mg protein for the medium type, and 47.7 mL/min/mg protein for the high type. Among the recombinant UGTs (13 isoforms) examined, UGT2B7 and UGT2B15 were the most active of catalyzing 4-tOP glucuronidation. Although the K m values of UGT2B7 and UGT2B15 were similar (0.36 and 0.42 µM, respectively), the CLint value of UGT2B7 (6.83 mL/min/mg protein) >UGT2B15 (2.35 mL/min/mg protein). Strong correlations were observed between the glucuronidation activities of 4-tOP and diclofenac (a probe for UGT2B7) or 4-hydroxybiphenyl (a probe for UGT2B15) with 0.79-0.88 of Spearman correlation coefficient (r s) values. These findings demonstrate that 4-tOP glucuronidation in humans is mainly catalyzed by hepatic UGT2B7 and UGT2B15, and suggest that these UGT isoforms play important and characteristic roles in the detoxification of 4-tOP.


Assuntos
Glucuronosiltransferase/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fenóis/farmacocinética , Adolescente , Adulto , Idoso , Compostos de Bifenilo/metabolismo , Compostos de Bifenilo/farmacocinética , Diclofenaco/farmacocinética , Disruptores Endócrinos/farmacocinética , Feminino , Glucuronídeos/metabolismo , Glucuronosiltransferase/genética , Humanos , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Pessoa de Meia-Idade , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
19.
Mol Pharm ; 14(6): 1883-1897, 2017 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-28402673

RESUMO

The present study was aimed to coencapsulate methotrexate (MTX) and aceclofenac (ACL) in fucose anchored lipid-polymer hybrid nanoparticles (Fu-LPHNPs) to achieve target specific and controlled delivery for developing therapeutic interventions against breast cancer. The effective combination therapy requires coadministration of drugs to achieve synergistic effect on tumor with minimum adverse effects. Present study investigates the potential of codelivery of MTX and ACL through LPHNPs in MCF-7 and triple negative breast cancer cells (MDA-MB-231). We obtained LPHNPs in the nanosize range (<150 nm) with better particle size distribution (<0.3). The entrapment and loading efficiency of MTX and ACL was calculated as 85-90% and 10-12%, respectively. The coumarin-6 LPHNP formulations showed rapid internalization within 2 h incubation with MCF-7 and MDA-MB-231 cells. With 8-10 times, greater bioavailability of drug-loaded LPHNPs than free MTX and ACL was obtained. Also, antitumor efficacy of MTX- and ACL-loaded LPHNPs was determined on DMBA-induced experimental breast cancer mouse model. This model showed better control over tumor growth with MTX- and ACL-loaded LPHNPs than the combination of MTX and ACL or MTX alone. ACL-loaded LPHNPs showed prophylactic and anticancer activity in DMBA-induced mouse model at higher dose (10 mg/kg). ACL-LPHNPs confer synergistic anticancer effect when administered in combination with MTX. In conclusion, ACL enhances the therapeutic and anticancer efficacy of MTX, when coencapsulated into fucose-anchored LPHNPs, as confirmed by cell viability and serum angiogenesis (IL-6, TNF-α, IL-1ß, COX2, and MMP1) at both transcript and proteome level.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Diclofenaco/análogos & derivados , Lipídeos/química , Metotrexato/administração & dosagem , Metotrexato/farmacocinética , Nanopartículas/química , Polímeros/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Diclofenaco/administração & dosagem , Diclofenaco/química , Diclofenaco/farmacocinética , Diclofenaco/farmacologia , Feminino , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Células MCF-7 , Metaloproteinase 1 da Matriz/metabolismo , Metotrexato/química , Metotrexato/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Fator de Necrose Tumoral alfa/metabolismo
20.
Drug Metab Dispos ; 45(7): 855-866, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28450578

RESUMO

In vitro hepatocyte culture systems have inherent limitations in capturing known human drug toxicities that arise from complex immune responses. Therefore, we established and characterized a liver immunocompetent coculture model and evaluated diclofenac (DCF) metabolic profiles, in vitro-in vivo clearance correlations, toxicological responses, and acute phase responses using liquid chromatography-tandem mass spectrometry. DCF biotransformation was assessed after 48 hours of culture, and the major phase I and II metabolites were similar to the in vivo DCF metabolism profile in humans. Further characterization of secreted bile acids in the medium revealed that a glycine-conjugated bile acid was a sensitive marker of dose-dependent toxicity in this three-dimensional liver microphysiological system. Protein markers were significantly elevated in the culture medium at high micromolar doses of DCF, which were also observed previously for acute drug-induced toxicity in humans. In this immunocompetent model, lipopolysaccharide treatment evoked an inflammatory response that resulted in a marked increase in the overall number of acute phase proteins. Kupffer cell-mediated cytokine release recapitulated an in vivo proinflammatory response exemplified by a cohort of 11 cytokines that were differentially regulated after lipopolysaccharide induction, including interleukin (IL)-1ß, IL-1Ra, IL-6, IL-8, IP-10, tumor necrosis factor-α, RANTES (regulated on activation normal T cell expressed and secreted), granulocyte colony-stimulating factor, macrophage colony-stimulating factor, macrophage inflammatory protein-1ß, and IL-5. In summary, our findings indicate that three-dimensional liver microphysiological systems may serve as preclinical investigational platforms from the perspective of the discovery of a set of clinically relevant biomarkers including potential reactive metabolites, endogenous bile acids, excreted proteins, and cytokines to predict early drug-induced liver toxicity in humans.


Assuntos
Proteínas de Fase Aguda/metabolismo , Anti-Inflamatórios não Esteroides , Citocinas/imunologia , Diclofenaco , Fígado/efeitos dos fármacos , Modelos Biológicos , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/toxicidade , Biotransformação , Técnicas de Cocultura , Diclofenaco/farmacocinética , Diclofenaco/toxicidade , Relação Dose-Resposta a Droga , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Inflamação , Células de Kupffer/citologia , Células de Kupffer/efeitos dos fármacos , Células de Kupffer/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/imunologia , Fígado/metabolismo , Ligação Proteica , Proteômica
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