The Experts below are selected from a list of 52125 Experts worldwide ranked by ideXlab platform
Per Artursson - One of the best experts on this subject based on the ideXlab platform.
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correlation of Drug Absorption with molecular surface properties
Journal of Pharmaceutical Sciences, 1996Co-Authors: Katrin Palm, Gert Strandlund, Kristina Luthman, Anna-lena Ungell, Per ArturssonAbstract:The correlation between dynamic surface properties of Drug molecules and Drug Absorption in two common in vitro models of the intestinal wall (Caco-2 monolayers and rat intestinal segments) has been investigated. A homologous series of β-adrenoreceptor antagonists were used as model compounds. Dynamic molecular surface properties, considering all low-energy conformations, of the compounds were calculated. The flexibility of the molecules was studied by molecular mechanics calculations (MM2) and the van der Waals' (vdW), and water accessible surface areas were calculated and averaged according to a Boltzmann distribution. Excellent correlations were obtained between the dynamic polar vdW surface areas and cell permeabilities in Caco-2 cells and rat ileum (r2 = 0.99 and 0.92, respectively). These correlations were stronger than those between calculated octanol/buffer partition coefficients (log Doct,7.4) and permeability (r2 = 0.80 and 0.73, respectively). Moreover, the calculated log Doct,7.4 values failed to rank the permeability coefficients through Caco-2 monolayers and rat ileum in the correct order. The results indicate that dynamic polar surface area is a promising alternative model for the prediction of oral Drug Absorption.
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a Drug Absorption model based on the mucus layer producing human intestinal goblet cell line ht29 h
Pharmaceutical Research, 1993Co-Authors: Agneta Wikman, Johan Karlsson, Ingemar Carlstedt, Per ArturssonAbstract:A new Drug Absorption model based on monolayers of the human intestinal goblet cell line HT29-H grown on permeable filters has been characterized. HT29-H cells have been shown (a) to form monolayers of mature goblet cells under standard cell culture conditions, (b) to secrete mucin molecules, (c) to produce a mucus layer that covers the apical cell surface, and (d) that this mucus layer is a significant barrier to the Absorption of the lipophilic Drug testosterone. This is the first demonstration of an intact human mucus layer with functional barrier properties produced in cell culture. The results indicate that monolayers of HT29-H cells provide a valuable complement to mucus-free Drug Absorption models based on absorptive cell lines such as Caco-2 cells.
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correlation between oral Drug Absorption in humans and apparent Drug permeability coefficients in human intestinal epithelial caco 2 cells
Biochemical and Biophysical Research Communications, 1991Co-Authors: Per Artursson, Johan KarlssonAbstract:Monolayers of a well differentiated human intestinal epithelial cell line, Caco-2, were used as a model to study passive Drug Absorption across the intestinal epithelium. Absorption rate constants (expressed as apparent permeability coefficients) were determined for 20 Drugs and peptides with different structural properties. The permeability coefficients ranged from approximately 5 × 10−8 to 5 × 10−5 cm/s. A good correlation was obtained between data on aral Absorption in humans and the results in the Caco-2 model. Drugs that are completely absorbed in humans had permeability coefficients > 1 × 10−6 cm/s. Drugs that are absorbed to > 1% but < 100% had permeability coefficients of 0.1−1.0 × 10−6 cm/s while Drugs and peptides that are absorbed to < 1% had permeability coefficients ≤ 1 × 10−7 cm/s. The results indicate that Caco-2 monolayers can be used as a model for studies on intestinal Drug Absorption.
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correlation between oral Drug Absorption in humans and apparent Drug permeability coefficients in human intestinal epithelial caco 2 cells
Biochemical and Biophysical Research Communications, 1991Co-Authors: Per Artursson, Johan KarlssonAbstract:Monolayers of a well differentiated human intestinal epithelial cell line, Caco-2, were used as a model to study passive Drug Absorption across the intestinal epithelium. Absorption rate constants (expressed as apparent permeability coefficients) were determined for 20 Drugs and peptides with different structural properties. The permeability coefficients ranged from approximately 5 x 10(-8) to 5 x 10(-5) cm/s. A good correlation was obtained between data on oral Absorption in humans and the results in the Caco-2 model. Drugs that are completely absorbed in humans had permeability coefficients greater than 1 x 10(-6) cm/s. Drugs that are absorbed to greater than 1% but less than 100% had permeability coefficients of 0.1-1.0 x 10(-6) cm/s while Drugs and peptides that are absorbed to less than 1% had permeability coefficients of less than or equal to 1 x 10(-7) cm/s. The results indicate that Caco-2 monolayers can be used as a model for studies on intestinal Drug Absorption.
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Cell cultures as models for Drug Absorption across the intestinal mucosa
Critical Reviews in Therapeutic Drug Carrier Systems, 1991Co-Authors: Per ArturssonAbstract:This review deals with cell culture models for studies of Drug Absorption across the intestinal mucosa. The selection of appropriate cells and cell culture conditions is discussed, guidelines for the characterization of the cell models are presented, and the intestinal barriers to Drug Absorption are discussed and compared with those in the cell culture models. Finally, recent applications of the cell culture models in Drug and peptide Absorption and metabolism studies are reviewed.
Johan Karlsson - One of the best experts on this subject based on the ideXlab platform.
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a Drug Absorption model based on the mucus layer producing human intestinal goblet cell line ht29 h
Pharmaceutical Research, 1993Co-Authors: Agneta Wikman, Johan Karlsson, Ingemar Carlstedt, Per ArturssonAbstract:A new Drug Absorption model based on monolayers of the human intestinal goblet cell line HT29-H grown on permeable filters has been characterized. HT29-H cells have been shown (a) to form monolayers of mature goblet cells under standard cell culture conditions, (b) to secrete mucin molecules, (c) to produce a mucus layer that covers the apical cell surface, and (d) that this mucus layer is a significant barrier to the Absorption of the lipophilic Drug testosterone. This is the first demonstration of an intact human mucus layer with functional barrier properties produced in cell culture. The results indicate that monolayers of HT29-H cells provide a valuable complement to mucus-free Drug Absorption models based on absorptive cell lines such as Caco-2 cells.
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correlation between oral Drug Absorption in humans and apparent Drug permeability coefficients in human intestinal epithelial caco 2 cells
Biochemical and Biophysical Research Communications, 1991Co-Authors: Per Artursson, Johan KarlssonAbstract:Monolayers of a well differentiated human intestinal epithelial cell line, Caco-2, were used as a model to study passive Drug Absorption across the intestinal epithelium. Absorption rate constants (expressed as apparent permeability coefficients) were determined for 20 Drugs and peptides with different structural properties. The permeability coefficients ranged from approximately 5 × 10−8 to 5 × 10−5 cm/s. A good correlation was obtained between data on aral Absorption in humans and the results in the Caco-2 model. Drugs that are completely absorbed in humans had permeability coefficients > 1 × 10−6 cm/s. Drugs that are absorbed to > 1% but < 100% had permeability coefficients of 0.1−1.0 × 10−6 cm/s while Drugs and peptides that are absorbed to < 1% had permeability coefficients ≤ 1 × 10−7 cm/s. The results indicate that Caco-2 monolayers can be used as a model for studies on intestinal Drug Absorption.
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correlation between oral Drug Absorption in humans and apparent Drug permeability coefficients in human intestinal epithelial caco 2 cells
Biochemical and Biophysical Research Communications, 1991Co-Authors: Per Artursson, Johan KarlssonAbstract:Monolayers of a well differentiated human intestinal epithelial cell line, Caco-2, were used as a model to study passive Drug Absorption across the intestinal epithelium. Absorption rate constants (expressed as apparent permeability coefficients) were determined for 20 Drugs and peptides with different structural properties. The permeability coefficients ranged from approximately 5 x 10(-8) to 5 x 10(-5) cm/s. A good correlation was obtained between data on oral Absorption in humans and the results in the Caco-2 model. Drugs that are completely absorbed in humans had permeability coefficients greater than 1 x 10(-6) cm/s. Drugs that are absorbed to greater than 1% but less than 100% had permeability coefficients of 0.1-1.0 x 10(-6) cm/s while Drugs and peptides that are absorbed to less than 1% had permeability coefficients of less than or equal to 1 x 10(-7) cm/s. The results indicate that Caco-2 monolayers can be used as a model for studies on intestinal Drug Absorption.
Patrick Augustijns - One of the best experts on this subject based on the ideXlab platform.
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impact of gastrointestinal physiology on Drug Absorption in special populations an ungap review
European Journal of Pharmaceutical Sciences, 2020Co-Authors: Cordula Stillhart, Patrick Augustijns, Hannah Batchelor, Abdul Basit, Katarina Vucicevic, Talia Flanagan, Ina Gesquiere, Rick Greupink, Daniel Keszthelyi, Mikko KoskinenAbstract:The release and Absorption profile of an oral medication is influenced by the physicochemical properties of the Drug and its formulation, as well as by the anatomy and physiology of the gastrointestinal (GI) tract. During Drug development the bioavailability of a new Drug is typically assessed in early clinical studies in a healthy adult population. However, many disease conditions are associated with an alteration of the anatomy and/or physiology of the GI tract. The same holds true for some subpopulations, such as paediatric or elderly patients, or populations with different ethnicity. The variation in GI tract conditions compared to healthy adults can directly affect the kinetics of Drug Absorption, and thus, safety and efficacy of an oral medication. This review provides an overview of GI tract properties in special populations compared to healthy adults and discusses how Drug Absorption is affected by these conditions. Particular focus is directed towards non-disease dependent conditions (age, sex, ethnicity, genetic factors, obesity, pregnancy), GI diseases (ulcerative colitis and Crohn's disease, celiac disease, cancer in the GI tract, Roux-en-Y gastric bypass, lactose intolerance, Helicobacter pylori infection, and infectious diseases of the GI tract), as well as systemic diseases that change the GI tract conditions (cystic fibrosis, diabetes, Parkinson's disease, HIV enteropathy, and critical illness). The current knowledge about GI conditions in special populations and their impact on Drug Absorption is still limited. Further research is required to improve confidence in pharmacokinetic predictions and dosing recommendations in the targeted patient population, and thus to ensure safe and effective Drug therapies.
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impact of regional differences along the gastrointestinal tract of healthy adults on oral Drug Absorption an ungap review
European Journal of Pharmaceutical Sciences, 2019Co-Authors: Maria Vertzoni, Mirko Koziolek, Patrick Augustijns, Michael Grimm, Glenn Lemmens, Neil Parrott, Christina Pentafragka, Christos Reppas, Jari Rubbens, Jens Van Den αbeeleAbstract:Oral administration is the most common route of Drug delivery. The Absorption of a Drug from the gut into the bloodstream involves disintegration of the solid dosage form, dissolution of the active pharmaceutical ingredient and its transport across the gut wall. The efficiency of these processes is determined by highly complex and dynamic interplay between the gastrointestinal tract, the dosage form and the API. The European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP) aims to improve our understanding of intestinal Drug Absorption by creating a multidisciplinary Network of researchers from academia and industry engaging in scientific discussions. As part of the basis for the UNGAP project, this review aims to summarize the current knowledge on anatomy and physiology of the human gastrointestinal tract with emphasis on human studies for the evaluation of the regional Drug Absorption and the prediction of oral dosage form performance. A range of factors and methods will be considered, including imaging methods, intraluminal sampling and, models for predicting segmental/regional Absorption. In addition, in vitro and in silico methods to evaluate regional Drug Absorption will be discussed. This will provide the basis for further work on improving predictions for the in vivo behavior of Drug products in the gastrointestinal tract.
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in situ perfusion in rodents to explore intestinal Drug Absorption challenges and opportunities
International Journal of Pharmaceutics, 2015Co-Authors: Jef Stappaerts, Joachim Brouwers, Pieter Annaert, Patrick AugustijnsAbstract:Abstract The in situ intestinal perfusion technique in rodents is a very important Absorption model, not only because of its predictive value, but it is also very suitable to unravel the mechanisms underlying intestinal Drug Absorption. This literature overview covers a number of specific applications for which the in situ intestinal perfusion set-up can be applied in favor of established in vitro Absorption tools, such as the Caco-2 cell model. Qualities including the expression of Drug transporters and metabolizing enzymes relevant for human intestinal Absorption and compatibility with complex solvent systems render the in situ technique the most designated Absorption model to perform transporter-metabolism studies or to evaluate the intestinal Absorption from biorelevant media. Over the years, the in situ intestinal perfusion model has exhibited an exceptional ability to adapt to the latest challenges in Drug Absorption profiling. For instance, the introduction of the mesenteric vein cannulation allows determining the appearance of compounds in the blood and is of great use, especially when evaluating the Absorption of compounds undergoing intestinal metabolism. Moreover, the use of the closed loop intestinal perfusion set-up is interesting when compounds or perfusion media are scarce. Compatibility with emerging trends in pharmaceutical profiling, such as the use of knockout or transgenic animals, generates unparalleled possibilities to gain mechanistic insight into specific Absorption processes. Notwithstanding the fact that the in situ experiments are technically challenging and relatively time-consuming, the model offers great opportunities to gain insight into the processes determining intestinal Drug Absorption.
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ex vivo permeability experiments in excised rat intestinal tissue and in vitro solubility measurements in aspirated human intestinal fluids support age dependent oral Drug Absorption
European Journal of Pharmaceutical Sciences, 2010Co-Authors: Pieter Annaert, Joachim Brouwers, Ann Bijnens, Frank Lammert, Patrick AugustijnsAbstract:Abstract The possible influence of advanced age on intestinal Drug Absorption was investigated by determining the effects of aging on (i) solubility of model Drugs in human intestinal fluids (HIF) obtained from two age groups (18–25 years; 62–72 years); and (ii) transepithelial permeation of model Drugs across intestinal tissue excised from young, adult and old rats. Average equilibrium solubility values for 10 poorly soluble compounds in HIF aspirated from both age groups showed high interindividual variability, but did not reveal significant differences. Characterization of the HIF from both age groups demonstrated comparable pH profiles, while concentrations of individual bile salts showed pronounced variability between individuals, however without statistical differences between age groups. Transepithelial permeation of the transcellular probe metoprolol was significantly increased in old rats (38 weeks) compared to the younger age groups, while the modulatory role of P-glycoprotein in transepithelial talinolol transport was observed in adult and old rats but not in young rats. In conclusion, age-dependent permeability of intestinal tissue (rather than age-dependent luminal Drug solubility) may contribute to altered intestinal Drug Absorption in older patients compared to young adults.
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in vitro screening models to assess intestinal Drug Absorption and metabolism
2008Co-Authors: S Deferme, Pieter Annaert, Patrick AugustijnsAbstract:Compounds intended for oral administration must have adequate biopharmaceutical properties in order to achieve therapeutic concentrations at the targeted site of action. Different models have been established for the parallel screening of these biopharmaceutical properties, including membrane-based models (PAMPA), cell culture-based models (such as Caco-2 and MDCK cell lines), and the Ussing chambers technique. In this chapter, the strengths and the drawbacks of these models are discussed, while examples of applications for these different models and suggestions to improve the models are provided. Finally, different in vitro methods for studying the intestinal metabolism are also described. As the intestinal Absorption process depends on a multitude of parameters, a single universal model accounting for all these parameters does not exist. Therefore, combination of different in vitro models should be considered in order to obtain better insights in intestinal Drug Absorption in the different phases of Drug discovery and development.
Hiroyuki Mizuguchi - One of the best experts on this subject based on the ideXlab platform.
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efficient generation of small intestinal epithelial like cells from human ipscs for Drug Absorption and metabolism studies
Stem cell reports, 2018Co-Authors: Ryosuke Negoro, Fuminori Sakurai, Kazuo Takayama, Kanae Kawai, Kazuo Harada, Kazumasa Hirata, Hiroyuki MizuguchiAbstract:The small intestine plays an important role in the Absorption and metabolism of oral Drugs. In the current evaluation system, it is difficult to predict the precise Absorption and metabolism of oral Drugs. In this study, we generated small intestinal epithelial-like cells from human induced pluripotent stem cells (hiPS-SIECs), which could be applied to Drug Absorption and metabolism studies. The small intestinal epithelial-like cells were efficiently generated from human induced pluripotent stem cell by treatment with WNT3A, R-spondin 3, Noggin, EGF, IGF-1, SB202190, and dexamethasone. The gene expression levels of small intestinal epithelial cell (SIEC) markers were similar between the hiPS-SIECs and human adult small intestine. Importantly, the gene expression levels of colonic epithelial cell markers in the hiPS-SIECs were much lower than those in human adult colon. The hiPS-SIECs generated by our protocol exerted various SIEC functions. In conclusion, the hiPS-SIECs can be utilized for evaluation of Drug Absorption and metabolism.
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generation of enterocyte like cells from human induced pluripotent stem cells for Drug Absorption and metabolism studies in human small intestine
Scientific Reports, 2015Co-Authors: Tatsuya Ozawa, Ryota Okamoto, Masashi Tachibana, Fuminori Sakurai, Ryosuke Negoro, Kazuo Takayama, Kenji Kawabata, Hiroyuki MizuguchiAbstract:Enterocytes play an important role in Drug Absorption and metabolism. However, a widely used enterocyte model, Caco-2 cell, has difficulty in evaluating both Drug Absorption and metabolism because the expression levels of some Drug Absorption and metabolism-related genes in these cells differ largely from those of human enterocytes. Therefore, we decided to generate the enterocyte-like cells from human induced pluripotent stem (iPS) cells (hiPS-ELCs), which are applicable to Drug Absorption and metabolism studies. The efficiency of enterocyte differentiation from human iPS cells was significantly improved by using EGF, SB431542 and Wnt3A and extending the differentiation period. The gene expression levels of cytochrome P450 3A4 (CYP3A4) and peptide transporter 1 in the hiPS-ELCs were higher than those in Caco-2 cells. In addition, CYP3A4 expression in the hiPS-ELCs was induced by treatment with 1, 25-dihydroxyvitamin D3 or rifampicin, which are known to induce CYP3A4 expression, indicating that the hiPS-ELCs have CYP3A4 induction potency. Moreover, the transendothelial electrical resistance (TEER) value of the hiPS-ELC monolayer was approximately 240 Ω*cm2, suggesting that the hiPS-ELC monolayer could form a barrier. In conclusion, we succeeded in establishing an enterocyte model from human iPS cells which have potential to be applied for Drug Absorption and metabolism studies.
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a novel strategy for the enhancement of Drug Absorption using a claudin modulator
Molecular Pharmacology, 2005Co-Authors: Masuo Kondoh, Hiroyuki Mizuguchi, Akane Masuyama, Azusa Takahashi, Nagayoshi Asano, Naoya Koizumi, Makiko Fujii, Takao Hayakawa, Yasuhiko Horiguchi, Yoshiteru WatanbeAbstract:Claudin, a tight junction integral membrane protein and a family of proteins, forms the actual sealing element of the tight junction. There are more than 20 members of the claudin family with different tissue-specific expression and barrier functions. Thus, a family of claudin may be a target for modifying the Absorption of Drugs. Here, we examined whether modulation of claudin could be used to enhance Drug Absorption. In the current studies, we used a C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) as a modulator of claudin-4. The Absorption of dextran was assessed in an in situ loop assay in rats to evaluate the Absorption-enhancing effects of C-CPE. Treatment with C-CPE dose-dependently enhanced the Absorption of dextran (mol. wt. 4000). These effects were not accompanied by injury of the intestinal mucosa as assessed by leakage of lactose dehydrogenase and histological observation. C-CPE was over 400-fold more potent at enhancing dextran Absorption than capric acid, a clinically used enhancer of Absorption. C-CPE interacted directly with claudin-4, and C-CPE lacking a part the C terminus neither bound claudin-4 nor enhanced Absorption in the rat jejunum. These results suggest that C-CPE enhances the Absorption of dextran in rat jejunum, apparently through interactions with claudin-4, and this effect may represent an effective novel strategy for enhancing the Absorption of Drugs.
Pieter Annaert - One of the best experts on this subject based on the ideXlab platform.
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in situ perfusion in rodents to explore intestinal Drug Absorption challenges and opportunities
International Journal of Pharmaceutics, 2015Co-Authors: Jef Stappaerts, Joachim Brouwers, Pieter Annaert, Patrick AugustijnsAbstract:Abstract The in situ intestinal perfusion technique in rodents is a very important Absorption model, not only because of its predictive value, but it is also very suitable to unravel the mechanisms underlying intestinal Drug Absorption. This literature overview covers a number of specific applications for which the in situ intestinal perfusion set-up can be applied in favor of established in vitro Absorption tools, such as the Caco-2 cell model. Qualities including the expression of Drug transporters and metabolizing enzymes relevant for human intestinal Absorption and compatibility with complex solvent systems render the in situ technique the most designated Absorption model to perform transporter-metabolism studies or to evaluate the intestinal Absorption from biorelevant media. Over the years, the in situ intestinal perfusion model has exhibited an exceptional ability to adapt to the latest challenges in Drug Absorption profiling. For instance, the introduction of the mesenteric vein cannulation allows determining the appearance of compounds in the blood and is of great use, especially when evaluating the Absorption of compounds undergoing intestinal metabolism. Moreover, the use of the closed loop intestinal perfusion set-up is interesting when compounds or perfusion media are scarce. Compatibility with emerging trends in pharmaceutical profiling, such as the use of knockout or transgenic animals, generates unparalleled possibilities to gain mechanistic insight into specific Absorption processes. Notwithstanding the fact that the in situ experiments are technically challenging and relatively time-consuming, the model offers great opportunities to gain insight into the processes determining intestinal Drug Absorption.
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ex vivo permeability experiments in excised rat intestinal tissue and in vitro solubility measurements in aspirated human intestinal fluids support age dependent oral Drug Absorption
European Journal of Pharmaceutical Sciences, 2010Co-Authors: Pieter Annaert, Joachim Brouwers, Ann Bijnens, Frank Lammert, Patrick AugustijnsAbstract:Abstract The possible influence of advanced age on intestinal Drug Absorption was investigated by determining the effects of aging on (i) solubility of model Drugs in human intestinal fluids (HIF) obtained from two age groups (18–25 years; 62–72 years); and (ii) transepithelial permeation of model Drugs across intestinal tissue excised from young, adult and old rats. Average equilibrium solubility values for 10 poorly soluble compounds in HIF aspirated from both age groups showed high interindividual variability, but did not reveal significant differences. Characterization of the HIF from both age groups demonstrated comparable pH profiles, while concentrations of individual bile salts showed pronounced variability between individuals, however without statistical differences between age groups. Transepithelial permeation of the transcellular probe metoprolol was significantly increased in old rats (38 weeks) compared to the younger age groups, while the modulatory role of P-glycoprotein in transepithelial talinolol transport was observed in adult and old rats but not in young rats. In conclusion, age-dependent permeability of intestinal tissue (rather than age-dependent luminal Drug solubility) may contribute to altered intestinal Drug Absorption in older patients compared to young adults.
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in vitro screening models to assess intestinal Drug Absorption and metabolism
2008Co-Authors: S Deferme, Pieter Annaert, Patrick AugustijnsAbstract:Compounds intended for oral administration must have adequate biopharmaceutical properties in order to achieve therapeutic concentrations at the targeted site of action. Different models have been established for the parallel screening of these biopharmaceutical properties, including membrane-based models (PAMPA), cell culture-based models (such as Caco-2 and MDCK cell lines), and the Ussing chambers technique. In this chapter, the strengths and the drawbacks of these models are discussed, while examples of applications for these different models and suggestions to improve the models are provided. Finally, different in vitro methods for studying the intestinal metabolism are also described. As the intestinal Absorption process depends on a multitude of parameters, a single universal model accounting for all these parameters does not exist. Therefore, combination of different in vitro models should be considered in order to obtain better insights in intestinal Drug Absorption in the different phases of Drug discovery and development.
