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1.
Bioorg Med Chem ; 23(13): 3831-42, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-25900628

RESUMO

Replacing hydrogen with deuterium as a means of altering ADME properties of drug molecules has recently enjoyed a renaissance, such that at least two deuterated chemical entities are currently in clinical development. Although most research in this area aims to increase the metabolic stability, and hence half-life of the active species, experience has shown that prediction of the in vivo behaviour of deuterated molecules is difficult and depends on multiple factors including the complexity of the metabolic scheme, the enzymes involved and hence the mechanism of the rate-determining step in the biotransformation. In an effort to elucidate some of these factors we examined the metabolic behaviour of two molecules from the Sanofi portfolio in a range of in vitro and in vivo systems. Although some key metabolic reactions of the acetylcholine release stimulator HP184 4 were slowed in vitro and in vivo when deuterium was present at the sites of metabolism, this did not translate to an increase in overall metabolic stability. By contrast, the tryptase inhibitor AVE5638 13 was much more metabolically stable in vitro in its deuterated form than when unlabelled. These results indicate that it could be of value to concentrate efforts in this area to molecules which are metabolised by a major pathway that involves enzymes of the amine oxidase family or other low-capacity enzyme families.


Assuntos
Agonistas Colinérgicos/sangue , Hepatócitos/metabolismo , Indóis/sangue , Piridinas/sangue , Inibidores da Tripsina/sangue , Animais , Biotransformação , Linhagem Celular , Agonistas Colinérgicos/farmacocinética , Deutério , Estabilidade de Medicamentos , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Humanos , Hidrogênio , Indóis/farmacocinética , Masculino , Monoaminoxidase/metabolismo , Piridinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Inibidores da Tripsina/farmacocinética
3.
J Pharm Pharmacol ; 71(11): 1663-1676, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31566757

RESUMO

OBJECTIVES: The main objective of the present work was to combine in-vitro and in-silico tools to better understand the in-vivo behavior of the immediate release (IR) formulation of zolpidem in the fasted and fed states. METHODS: The dissolution of zolpidem was evaluated using biorelevant media simulating the gastric and intestinal environment in the fasted and fed states. Additionally, the influence of high viscosity and high fat content on the release of zolpidem under fed state conditions was investigated. The in-vitro results were combined with a physiologically based pharmacokinetic (PBPK) model constructed with Simcyp® to simulate the zolpidem pharmacokinetic profile in both prandial states. KEY FINDINGS: In vitro biorelevant dissolution experiments representing the fasted and fed states, combinedwith PBPKmodelling, were able to simulate the plasma profiles from the clinical food effect studies well. Experiments reflecting the pH and fat content of themeal led to a good prediction of the zolpidem plasma profile in the fed state, whereas increasing the viscosity of the gastricmedia led to an under-prediction. CONCLUSIONS: This work demonstrates that the combination of biorelevant dissolution testing and PBPK modelling is very useful for understanding the in-vivo behavior of zolpidem in the fasted and fed states. This approach could be implemented in the development of other drugs exhibiting negative food effects, saving resources and bringing new drug products to the market faster.


Assuntos
Interações Alimento-Droga/fisiologia , Comprimidos/farmacocinética , Zolpidem/farmacocinética , Administração Oral , Adolescente , Adulto , Simulação por Computador , Jejum/fisiologia , Esvaziamento Gástrico/fisiologia , Humanos , Absorção Intestinal/fisiologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Solubilidade/efeitos dos fármacos , Adulto Jovem
4.
Eur J Pharm Sci ; 96: 598-609, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27671970

RESUMO

Predicting oral bioavailability (Foral) is of importance for estimating systemic exposure of orally administered drugs. Physiologically-based pharmacokinetic (PBPK) modelling and simulation have been applied extensively in biopharmaceutics recently. The Oral Biopharmaceutical Tools (OrBiTo) project (Innovative Medicines Initiative) aims to develop and improve upon biopharmaceutical tools, including PBPK absorption models. A large-scale evaluation of PBPK models may be considered the first step. Here we characterise the OrBiTo active pharmaceutical ingredient (API) database for use in a large-scale simulation study. The OrBiTo database comprised 83 APIs and 1475 study arms. The database displayed a median logP of 3.60 (2.40-4.58), human blood-to-plasma ratio of 0.62 (0.57-0.71), and fraction unbound in plasma of 0.05 (0.01-0.17). The database mainly consisted of basic compounds (48.19%) and Biopharmaceutics Classification System class II compounds (55.81%). Median human intravenous clearance was 16.9L/h (interquartile range: 11.6-43.6L/h; n=23), volume of distribution was 80.8L (54.5-239L; n=23). The majority of oral formulations were immediate release (IR: 87.6%). Human Foral displayed a median of 0.415 (0.203-0.724; n=22) for IR formulations. The OrBiTo database was found to be largely representative of previously published datasets. 43 of the APIs were found to satisfy the minimum inclusion criteria for the simulation exercise, and many of these have significant gaps of other key parameters, which could potentially impact the interpretability of the simulation outcome. However, the OrBiTo simulation exercise represents a unique opportunity to perform a large-scale evaluation of the PBPK approach to predicting oral biopharmaceutics.


Assuntos
Biofarmácia/métodos , Bases de Dados Factuais , Modelos Biológicos , Preparações Farmacêuticas/metabolismo , Administração Oral , Avaliação Pré-Clínica de Medicamentos/métodos , Previsões , Humanos , Absorção Intestinal/efeitos dos fármacos , Absorção Intestinal/fisiologia , Preparações Farmacêuticas/administração & dosagem
5.
Bioanalysis ; 7(6): 653-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25514576

RESUMO

AIMS: A cross-laboratory experiment has been performed on a novel dried blood sampler in order to investigate whether it overcomes issues associated with blood volume and hematocrit (HCT) that are observed when taking a subpunch from dried blood spot samples. MATERIALS & METHODS: An average blood volume of 10.6 µl was absorbed by the samplers across the different HCTs investigated (20-65%). RESULTS: No notable change of volume absorbed was noted across the HCT range. Furthermore, the variation in blood sample volumes across six different laboratories was within acceptable limits. CONCLUSION: The novel volumetric absorptive microsampling device has the potential to deliver the advantages of dried blood spot sampling while overcoming some of the issues associated with the technology.


Assuntos
Coleta de Amostras Sanguíneas/instrumentação , Teste em Amostras de Sangue Seco/instrumentação , Hematócrito , Absorção Fisico-Química , Animais , Artefatos , Humanos , Ratos
6.
Eur J Pharm Sci ; 57: 99-151, 2014 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-24637348

RESUMO

This review summarizes the current knowledge on anatomy and physiology of the human gastrointestinal tract in comparison with that of common laboratory animals (dog, pig, rat and mouse) with emphasis on in vivo methods for testing and prediction of oral dosage form performance. A wide range of factors and methods are considered in addition, such as imaging methods, perfusion models, models for predicting segmental/regional absorption, in vitro in vivo correlations as well as models to investigate the effects of excipients and the role of food on drug absorption. One goal of the authors was to clearly identify the gaps in today's knowledge in order to stimulate further work on refining the existing in vivo models and demonstrate their usefulness in drug formulation and product performance testing.


Assuntos
Biofarmácia/métodos , Excipientes/química , Interações Alimento-Droga , Trato Gastrointestinal/metabolismo , Absorção Intestinal , Preparações Farmacêuticas/metabolismo , Farmacocinética , Administração Oral , Animais , Química Farmacêutica , Motilidade Gastrointestinal , Humanos , Modelos Animais , Modelos Biológicos , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/química , Reprodutibilidade dos Testes , Especificidade da Espécie
7.
Bioanalysis ; 2(8): 1469-75, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21083347

RESUMO

BACKGROUND: Dried blood spot (DBS) sampling could potentially become the preferred blood collection technique in toxicological and clinical studies. Autoradiography was performed to study compound distribution within a dbs under different conditions using five papers, 31ETF, Grade 226, 903(®), FTA(®) and FTA(®) Elute. RESULTS: The results showed an uneven distribution in all papers with common distribution patterns regardless of compounds: decreased concentrations along the edge, the volcano effect in the middle and the speckle pattern in the center. Treated papers were more readily influenced by environmental factors. CONCLUSION: Autoradiography enables visualization of a compound's distribution and can guide bioanalytical assay development by allowing convenient evaluation of factors, such as choice of paper, spotting volume, punch size, punch location, temperature and humidity.


Assuntos
Análise Química do Sangue/métodos , Coleta de Amostras Sanguíneas/instrumentação , Papel , Radioatividade , Adulto , Coagulação Sanguínea , Fenômenos Químicos , Dessecação , Hematócrito , Humanos , Umidade , Laboratórios , Masculino , Temperatura
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