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1.
Adv Exp Med Biol ; 1141: 1-12, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571163

RESUMO

Absorption, distribution, and excretion of drugs are involved in drug transport across plasma membrane, most of which are mediated by drug transporters. These drug transporters are generally divided into solute carrier (SLC) family and ATP-binding cassette (ABC) family. These transporters not only mediate transport of therapeutic drugs across membrane but also transport various kinds of endogenous compounds. Thus besides being participated in disposal of drug and its clinical efficacy/toxicity, these transporters also play vital roles in maintaining cell homeostasis via regulating transport of endogenous compounds. This chapter will outline classification of drug transporters, their roles in drug disposal/drug response, and remote communication between tissues/organs.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Proteínas Carreadoras de Solutos , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Transporte Biológico , Comunicação Celular , Membrana Celular/metabolismo , Humanos , Preparações Farmacêuticas/metabolismo , Proteínas Carreadoras de Solutos/metabolismo
2.
Adv Exp Med Biol ; 1141: 101-202, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571165

RESUMO

Solute carrier (SLC) family transporters utilize an electrochemical potential difference or an ion gradient generated by primary active transporters for transporting their substrates across biological membranes. These transporters are categorized as facilitated transporters or secondary active transporters. More than 300 SLC transporters have been identified. SLC transporters related to drug transport mainly include SLC21 gene subfamily (organic anion-transporting polypeptides, OATPs), SLC22A gene subfamily (organic anion transporters, OATs; organic cation transporters, OCTs; or organic cation/carnitine transporters, OCTNs), SLC15A gene subfamily (peptide transporters, PEPTs), and SLC47A gene subfamily (multidrug and toxin extrusion, MATEs). In general, OCTs transport organic cations, OATPs transport large and fairly hydrophobic organic anions, OATs transport the smaller and more hydrophilic organic anions, and PEPTs are responsible for the uptake of di-/tripeptides and peptide-like drugs. MATEs are responsible for efflux of organic cations. These transporters also transport some endogenous substances, indicating that the dysfunction of SLCs not only disrupts homeostasis but also largely impacts on the disposition of their substrate drugs. This chapter will discuss these SLC family transporters, with an emphasis on tissue distribution, substrate specificity, transporter physiology, and clinical significance.


Assuntos
Proteínas Carreadoras de Solutos , Animais , Cátions/metabolismo , Humanos , Peptídeos/metabolismo , Preparações Farmacêuticas/metabolismo , Proteínas Carreadoras de Solutos/metabolismo , Especificidade por Substrato , Distribuição Tecidual/fisiologia
3.
Adv Exp Med Biol ; 1141: 241-291, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571167

RESUMO

Drug transporters are considered to be determinants of drug disposition and effects/toxicities by affecting the absorption, distribution, and excretion of drugs. Drug transporters are generally divided into solute carrier (SLC) family and ATP binding cassette (ABC) family. Widely studied ABC family transporters include P-glycoprotein (P-GP), breast cancer resistance protein (BCRP), and multidrug resistance proteins (MRPs). SLC family transporters related to drug transport mainly include organic anion-transporting polypeptides (OATPs), organic anion transporters (OATs), organic cation transporters (OCTs), organic cation/carnitine transporters (OCTNs), peptide transporters (PEPTs), and multidrug/toxin extrusions (MATEs). These transporters are often expressed in tissues related to drug disposition, such as the small intestine, liver, and kidney, implicating intestinal absorption of drugs, uptake of drugs into hepatocytes, and renal/bile excretion of drugs. Most of therapeutic drugs are their substrates or inhibitors. When they are comedicated, serious drug-drug interactions (DDIs) may occur due to alterations in intestinal absorption, hepatic uptake, or renal/bile secretion of drugs, leading to enhancement of their activities or toxicities or therapeutic failure. This chapter will illustrate transporter-mediated DDIs (including food drug interaction) in human and their clinical significances.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Interações de Medicamentos , Preparações Farmacêuticas , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Transporte Biológico , Interações Alimento-Droga , Humanos , Proteínas de Neoplasias/metabolismo , Transportadores de Ânions Orgânicos , Preparações Farmacêuticas/metabolismo
4.
Adv Exp Med Biol ; 1141: 293-340, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571168

RESUMO

Hepatic drug transporters are mainly distributed in parenchymal liver cells (hepatocytes), contributing to drug's liver disposition and elimination. According to their functions, hepatic transporters can be roughly divided into influx and efflux transporters, translocating specific molecules from blood into hepatic cytosol and mediating the excretion of drugs and metabolites from hepatic cytosol to blood or bile, respectively. The function of hepatic transport systems can be affected by interspecies differences and inter-individual variability (polymorphism). In addition, some drugs and disease can redistribute transporters from the cell surface to the intracellular compartments, leading to the changes in the expression and function of transporters. Hepatic drug transporters have been associated with the hepatic toxicity of drugs. Gene polymorphism of transporters and altered transporter expressions and functions due to diseases are found to be susceptible factors for drug-induced liver injury (DILI). In this chapter, the localization of hepatic drug transporters, their regulatory factors, physiological roles, and their roles in drug's liver disposition and DILI are reviewed.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Proteínas de Membrana Transportadoras , Preparações Farmacêuticas , Transporte Biológico , Variação Genética , Hepatócitos , Humanos , Proteínas de Membrana Transportadoras/genética , Preparações Farmacêuticas/metabolismo
5.
Adv Exp Med Biol ; 1141: 341-360, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571169

RESUMO

The kidney plays an important role in maintaining total body homeostasis and eliminating toxic xenobiotics and metabolites. Numerous drugs and their metabolites are ultimately eliminated in the urine. The reabsorption and secretion functions of the nephron are mediated by a variety of transporters located in the basolateral and luminal membranes of the tubular cells. In the past decade, many studies indicated that transporters play important roles in drug pharmacokinetics and demonstrated the impact of renal transporters on the disposition of drugs, drug-drug interactions, and nephrotoxicities. Here, we focus on several important renal transporters and their roles in drug elimination and disposition, drug-induced nephrotoxicities and potential clinical solutions.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Rim , Proteínas de Membrana Transportadoras , Preparações Farmacêuticas , Animais , Transporte Biológico , Interações de Medicamentos , Humanos , Inativação Metabólica , Rim/efeitos dos fármacos , Preparações Farmacêuticas/metabolismo
6.
Adv Exp Med Biol ; 1141: 361-405, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571170

RESUMO

Oral drug administration is the most favorable route of drug administration in the clinic. Intestinal transporters have been shown to play a significant role in the rate and extent of drug absorption of some, but not all, drug molecules. Due to the heterogeneous expression of multiple transporters along the intestine, the preferential absorption sites for drugs may vary significantly. In this chapter, we aim to summarize the current research on the expression, localization, function, and regulation of human intestinal transporters implicated in altering the absorption of low to medium molecular weight drug molecules. The role played by bile acid transport proteins (e.g., ASBT and OST-α/ß) is included in the discussion. The synergistic action of intestinal drug metabolism and transport is also discussed. Despite the complicated regulatory factors, the biopharmaceutics drug disposition classification system (BDDCS) put forward by Wu and Benet may help us better predict the effect of transporters on drug absorption. The drug-induced toxicity in the intestine, which may result from drug-drug interaction, gut microbiota, and bile salt toxicity, is also discussed.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Absorção Intestinal , Intestinos , Proteínas de Membrana Transportadoras , Preparações Farmacêuticas , Interações de Medicamentos , Humanos , Intestinos/efeitos dos fármacos , Preparações Farmacêuticas/metabolismo
7.
Adv Exp Med Biol ; 1141: 407-466, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571171

RESUMO

Blood-brain interfaces comprise the cerebral microvessel endothelium forming the blood-brain barrier (BBB) and the epithelium of the choroid plexuses forming the blood-cerebrospinal fluid barrier (BCSFB). Their main functions are to impede free diffusion between brain fluids and blood; to provide transport processes for essential nutrients, ions, and metabolic waste products; and to regulate the homeostasis of central nervous system (CNS), all of which are attributed to absent fenestrations, high expression of tight junction proteins at cell-cell contacts, and expression of multiple transporters, receptors, and enzymes. Existence of BBB is an important reason that systemic drug administration is not suitable for the treatment of CNS diseases. Some diseases, such epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and diabetes, alter BBB function via affecting tight junction proteins or altering expression and function of these transporters. This chapter will illustrate function of BBB, expression of transporters, as well as their alterations under disease status.


Assuntos
Barreira Hematoencefálica , Proteínas de Membrana Transportadoras , Preparações Farmacêuticas , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Humanos , Proteínas de Membrana Transportadoras/metabolismo , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo
8.
Pharm Res ; 36(11): 155, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31485804

RESUMO

PURPOSE: The purpose of this study was to determine the impact of food on gastric pH and the ability of over the counter betaine hydrochloride (BHCl) acid to reacidify gastric pH after food-induced elevations in gastric pH. METHODS: This open-label cross over clinical study (NCT02758015) included 9 subjects who were randomly assigned to one of 16 possible, 4-period cross-over sequences to determine the impact and relationship of food and gastric pH with acid supplementation. Subjects were administered various doses (1500 mg, 3000 mg and 4500 mg) of betaine hydrochloride (BHCl) to determine the ability of acid supplementation to reacidify gastric pH after the elevation of gastric pH caused by the ingestion of food. RESULTS: Following the administration of food and the resulting elevation in gastric pH, time to return to baseline gastric pH levels without acid supplementation was 49.7 ± 14.0 min. Administering 4500 mg of BHCl acid in capsules was able to reacidify gastric pH levels back to baseline following the administration of food in approximately 17.3 ± 5.9 min. AUCpH of each treatment were similar and not statistically different. Mean max pH following the administration of food was 3.20 ± 0.55. CONCLUSION: The ability of food to elevate and maintain gastric pH levels in the presence of acid supplementation was made evident throughout the study. A 4500 mg dose of BHCl was required to reacidify gastric pH after the administration of food. This study details the difficulty faced by clinicians in dosing a poorly soluble, weakly basic drug to patients receiving acid reducing agents where administration with food is recommended to avoid gastric side effects. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02758015.


Assuntos
Betaína/uso terapêutico , Alimentos , Absorção Gástrica , Ácido Gástrico/metabolismo , Fármacos Gastrointestinais/uso terapêutico , Preparações Farmacêuticas/metabolismo , Administração Oral , Adolescente , Adulto , Estudos Cross-Over , Feminino , Interações Alimento-Droga , Determinação da Acidez Gástrica , Humanos , Concentração de Íons de Hidrogênio , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
10.
Pharm Res ; 36(10): 148, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31414302

RESUMO

Medications have been used during space missions for more than half a century, yet our understanding of the effects of spaceflight on drug pharmacokinetics and pharmacodynamics is poor. The space environment induces time-dependent alterations in human physiology that include fluid shifts, cardiovascular deconditioning, bone and muscle density loss, and impaired immunity. This review presents the current knowledge on the physiological effects of spaceflight that can translate into altered drug disposition and activity and eventually to inadequate treatment. It describes findings from studies in astronauts along with mechanistic studies in animal models and in vitro systems. Future missions into deeper space and the emergence of commercial spaceflight will require a more detailed understanding of space pharmacology to optimize treatment in astronauts and space travelers.


Assuntos
Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Medicina Aeroespacial , Animais , Astronautas , Gravitação , Humanos , Farmacocinética , Voo Espacial , Ausência de Peso/efeitos adversos
11.
BMC Bioinformatics ; 20(1): 437, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438848

RESUMO

BACKGROUND: Batch effects were not accounted for in most of the studies of computational drug repositioning based on gene expression signatures. It is unknown how batch effect removal methods impact the results of signature-based drug repositioning. Herein, we conducted differential analyses on the Connectivity Map (CMAP) database using several batch effect correction methods to evaluate the influence of batch effect correction methods on computational drug repositioning using microarray data and compare several batch effect correction methods. RESULTS: Differences in average signature size were observed with different methods applied. The gene signatures identified by the Latent Effect Adjustment after Primary Projection (LEAPP) method and the methods fitted with Linear Models for Microarray Data (limma) software demonstrated little agreement. The external validity of the gene signatures was evaluated by connectivity mapping between the CMAP database and the Library of Integrated Network-based Cellular Signatures (LINCS) database. The results of connectivity mapping indicate that the genes identified were not reliable for drugs with total sample size (drug + control samples) smaller than 40, irrespective of the batch effect correction method applied. With total sample size larger than 40, the methods correcting for batch effects produced significantly better results than the method with no batch effect correction. In a simulation study, the power was generally low for simulated data with sample size smaller than 40. We observed best performance when using the limma method correcting for two principal components. CONCLUSION: Batch effect correction methods strongly impact differential gene expression analysis when the sample size is large enough to contain sufficient information and thus the downstream drug repositioning. We recommend including two or three principal components as covariates in fitting models with limma when sample size is sufficient (larger than 40 drug and controls combined).


Assuntos
Biologia Computacional/métodos , Preparações Farmacêuticas/metabolismo , Transcriptoma , Simulação por Computador , Bases de Dados Factuais , Reposicionamento de Medicamentos , Humanos , Análise de Componente Principal , Tamanho da Amostra
12.
Nihon Yakurigaku Zasshi ; 154(1): 28-34, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31308347

RESUMO

Drug metabolism is an important determinant to control pharmacokinetics, drug response and drug toxicity. Large variabilities are observed in expression or activity of drug-metabolizing enzymes such as cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Therefore, understanding of the causes for the variation of drug metabolism potencies is essential for efficient drug development and promotion of safe use of medicines. The expression of drug-metabolizing enzymes is controlled by transcriptional regulation by nuclear receptors and transcriptional factors, and by epigenetic regulation such as DNA methylation and histone acetylation. In addition to such regulatory mechanisms, recent studies revealed that microRNAs (miRNAs) significantly contribute to post-transcriptional regulation of drug-metabolizing enzymes. miRNAs are endogenous ~22-nucleotide non-coding RNAs that regulate gene expression through the translational repression and degradation of mRNAs. More recently, it has been clarified that the presence of pseudogenes or single nucleotide polymorphisms as well as RNA editing event affect miRNA-dependent regulation. It is unwavering fact that miRNAs significantly contribute to inter- and intra-individual differences in the expression of drug-metabolizing enzymes. In this review, we introduce current knowledge of miRNA-mediated regulation of drug metabolism.


Assuntos
Inativação Metabólica , MicroRNAs/genética , Preparações Farmacêuticas/metabolismo , Epigênese Genética , Edição de Genes , Regulação da Expressão Gênica , Humanos , Polimorfismo de Nucleotídeo Único , Receptores Citoplasmáticos e Nucleares
13.
BMC Bioinformatics ; 20(Suppl 13): 383, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31337333

RESUMO

BACKGROUND: Drug repurposing has been motivated to ameliorate low probability of success in drug discovery. For the recent decade, many in silico attempts have received primary attention as a first step to alleviate the high cost and longevity. Such study has taken benefits of abundance, variety, and easy accessibility of pharmaceutical and biomedical data. Utilizing the research friendly environment, in this study, we propose a network-based machine learning algorithm for drug repurposing. Particularly, we show a framework on how to construct a drug network, and how to strengthen the network by employing multiple/heterogeneous types of data. RESULTS: The proposed method consists of three steps. First, we construct a drug network from drug-target protein information. Then, the drug network is reinforced by utilizing drug-drug interaction knowledge on bioactivity and/or medication from literature databases. Through the enhancement, the number of connected nodes and the number of edges between them become more abundant and informative, which can lead to a higher probability of success of in silico drug repurposing. The enhanced network recommends candidate drugs for repurposing through drug scoring. The scoring process utilizes graph-based semi-supervised learning to determine the priority of recommendations. CONCLUSIONS: The drug network is reinforced in terms of the coverage and connections of drugs: the drug coverage increases from 4738 to 5442, and the drug-drug associations as well from 808,752 to 982,361. Along with the network enhancement, drug recommendation becomes more reliable: AUC of 0.89 was achieved lifted from 0.79. For typical cases, 11 recommended drugs were shown for vascular dementia: amantadine, conotoxin GV, tenocyclidine, cycloeucine, etc.


Assuntos
Reposicionamento de Medicamentos/métodos , Preparações Farmacêuticas/química , Área Sob a Curva , Interações de Medicamentos , Humanos , Preparações Farmacêuticas/metabolismo , Proteínas/química , Proteínas/metabolismo , Curva ROC , Aprendizado de Máquina Supervisionado
14.
Expert Opin Drug Metab Toxicol ; 15(8): 633-658, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31274340

RESUMO

Introduction: In quantitative modeling, the resolving of underpredictions and overpredictions of hepatic clearance (CLh) makes a top priority for pharmacokinetic modelers. Clearly, the 'protein-mediated hepatic uptake' is a violation of 'the free drug hypothesis', but the lack of its consideration in CLh-predictive approaches may be one of the reasons to explain the discrepancies between predicted and observed values. Areas covered: We first review the two 'albumin-facilitated hepatic uptake' models that were recently challenged to improve the in vitro-to-in vivo extrapolation (IVIVE) of CLh by reducing the underprediction bias, particularly in the absence of albumin (ALB) in vitro compared to the presence of ALB in vivo. Second, we identify three types of interactions related to the ALB-bound drug moiety (i.e., ALB-lipids, ALB-proteins, and ALB-ligand allosteric interactions) that may be behind the 'ALB-mediated hepatic uptake' mechanism(s) for highly bound drugs. Main keywords used in our search are IVIVE; albumin; allostery; protein-mediated uptake; hepatic clearance; polarized hepatocytes. Expert opinion: Understanding the implication of these interactions and the enzyme/transporter interplay for each drug would help selecting the appropriate IVIVE model. Therefore, we have proposed a tree of decision for guidance. The next step is to improve the 'ALB-facilitated hepatic uptake' models to cover the remaining uncertainties.


Assuntos
Albuminas/metabolismo , Hepatócitos/metabolismo , Modelos Biológicos , Transporte Biológico , Humanos , Lipídeos/química , Fígado/metabolismo , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Farmacocinética , Ligação Proteica , Proteínas/metabolismo
15.
Chem Commun (Camb) ; 55(63): 9241-9250, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31328738

RESUMO

The field of chemical biology has introduced several approaches, typically using chemical probes, to measure the direct binding interaction of a small molecule with its biological target in cells. The use of these direct target engagement assays in pharmaceutical development can support mechanism of action hypothesis testing, rank ordering of compounds, and iterative improvements of chemical matter. This Feature Article highlights a newer application of these approaches: the quantification of target engagement in animal models to support late stage preclinical development and the nomination of a drug candidate to clinical trials. Broadly speaking, these efforts can be divided between compounds that covalently and reversibly interact with protein targets; recent examples for both categories are discussed for a range of targets, along with their limitations. New, promising technologies are also highlighted, in addition to the application of target engagement determination to new therapeutic modalities.


Assuntos
Modelos Animais , Preparações Farmacêuticas/metabolismo , Animais , Interações de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Preparações Farmacêuticas/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética
17.
Arch Environ Contam Toxicol ; 77(2): 155-161, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31168646

RESUMO

Environmental pollution caused by pharmaceuticals and their transformation products (TPs) has become an increasingly important concern, due to the increased use of pharmaceutical formulations exposed to environmental change. Considerable concerns have been raised regarding potential toxic effects of the transformation products of pharmaceutical formulations on human health. Environmental risk assessments are mostly based on one active component, which causes different ecotoxicological effects, albeit the particular component is present in the environment as a part of a multicomponent mixture with different pharmaceuticals and excipients. The purpose of this review was to present the insight and new knowledge recently obtained by studies on the risk of pharmaceutical formulations, including all contained excipients, pharmaceuticals, and their transformation products exposed to the environment. Numerous studies have shown that the level of pharmaceuticals in the environment is below toxic concentration; however, long exposure to very low concentrations can still lead to harmful concentrations in biota. Accordingly, the findings of this study are expected to highlight the existing issues of the effect of pharmaceutical formulations to the environment, including TPs, and help to determine future research directions towards accumulating the data and improving ecological risk assessment.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Ecotoxicologia , Preparações Farmacêuticas/análise , Preparações Farmacêuticas/química , Animais , Biodegradação Ambiental , Poluição Ambiental , Humanos , Preparações Farmacêuticas/metabolismo , Processos Fotoquímicos , Medição de Risco , Eliminação de Resíduos Líquidos , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/química , Poluentes Químicos da Água/metabolismo
18.
Pharm Res ; 36(8): 113, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31152241

RESUMO

PURPOSE: To examine the interlaboratory variability in CLint values generated with human hepatocytes and determine trends in variability and clearance prediction accuracy using physicochemical and pharmacokinetic parameters. METHODS: Data for 50 compounds from 14 papers were compiled with physicochemical and pharmacokinetic parameter values taken from various sources. RESULTS: Coefficients of variation were as high as 99.8% for individual compounds and variation was not dependent on the number of prediction values included in the analysis. When examining median values, it appeared that compounds with a lower number of rotatable bonds had more variability. When examining prediction uniformity, those compounds with uniform in vivo underpredictions had higher CLint, in vivo values, while those with non-uniform predictions typically had lower CLint, in vivo values. Of the compounds with uniform predictions, only a small number were uniformly predicted accurately. Based on this limited dataset, less lipophilic, lower intrinsic clearance, and lower protein binding compounds yield more accurate clearance predictions. CONCLUSIONS: Caution should be taken when compiling in vitro CLint values from different laboratories as variations in experimental procedures (such as extent of shaking during incubation) may yield different predictions for the same compound. The majority of compounds with uniform in vitro values had predictions that were inaccurate, emphasizing the need for a better mechanistic understanding of IVIVE. The non-uniform predictions, often with low turnover compounds, reaffirmed the experimental challenges for drugs in this clearance range. Separating new chemical entities by lipophilicity, intrinsic clearance, and protein binding may help instill more confidence in IVIVE predictions.


Assuntos
Hepatócitos/metabolismo , Preparações Farmacêuticas/metabolismo , Farmacocinética , Fenômenos Químicos , Biologia Computacional , Bases de Dados de Produtos Farmacêuticos , Humanos , Taxa de Depuração Metabólica , Microssomos Hepáticos/metabolismo , Modelos Biológicos , Preparações Farmacêuticas/química , Ligação Proteica
19.
Curr Med Chem ; 26(24): 4681-4696, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31203795

RESUMO

Phytochemicals represent an important class of bioactive compounds characterized by significant health benefits. Notwithstanding these important features, their potential therapeutic properties suffer from poor water solubility and membrane permeability limiting their approach to nutraceutical and pharmaceutical applications. Lipid nanoparticles are well known carrier systems endowed with high biodegradation and an extraordinary biocompatible chemical nature, successfully used as platform for advanced delivery of many active compounds, including the oral, topical and systemic routes. This article is aimed at reviewing the last ten years of studies about the application of lipid nanoparticles in active natural compounds reporting examples and advantages of these colloidal carrier systems.


Assuntos
Portadores de Fármacos/química , Lipídeos/química , Nanopartículas/química , Humanos , Nanomedicina , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Solubilidade
20.
J Chromatogr A ; 1601: 164-170, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31047660

RESUMO

The application of two-dimensional liquid chromatography (2D-LC) is gradually growing also in the area of metabolite profiling and identification. The current contribution describes a heartcut 2D-UHPLC configuration that is applied in support of drug metabolism studies in development. The setup applies four LC columns: two analytical UHPLC columns to perform the first and second dimension separations, which are both preceded by a short HPLC column operated as trapping column. The first HPLC column allows a significant online preconcentration by large volume injection. The second short HPLC column is placed between the first and second dimension columns and enables the selection of orthogonal conditions in the second dimension independent of the first dimension making the heartcutting 2D approach more generic. The value of the setup was demonstrated with selective ultraviolet chromatograms obtained for the two major hydroxylated metabolites of atorvastatin separating them from a very high biological background, originating from an injection of 4 mL feces extract, by heartcut 2D-LC. In a second application, the main metabolite of imipramine was baseline separated from some minor metabolites that were co-eluting in the first dimension, allowing accurate and sensitive quantification. A quantification limit in the attogram/mL range was achieved thanks to the injection of 200 mL diluted urine, corresponding to 100 mL urine on column.


Assuntos
Técnicas de Química Analítica/métodos , Cromatografia Líquida de Alta Pressão , Preparações Farmacêuticas/análise , Animais , Atorvastatina/análise , Atorvastatina/metabolismo , Cães , Fezes/química , Humanos , Imipramina/análise , Imipramina/metabolismo , Preparações Farmacêuticas/metabolismo , Preparações Farmacêuticas/urina , Urina/química
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