In Vivo Mechanisms of Intestinal Drug Absorption from Aprepitant Nanoformulations

2017 ◽  
Vol 14 (12) ◽  
pp. 4233-4242 ◽  
Author(s):  
Carl Roos ◽  
David Dahlgren ◽  
Staffan Berg ◽  
Jan Westergren ◽  
Bertil Abrahamsson ◽  
...  
Keyword(s):  
Drug Absorption ◽  
Intestinal Drug Absorption

scholarly journals Bacterial metabolism rescues the inhibition of intestinal drug absorption by food and drug additives

2020 ◽  
Vol 117 (27) ◽  
pp. 16009-16018 ◽  
Author(s):  
Ling Zou ◽  
Peter Spanogiannopoulos ◽  
Lindsey M. Pieper ◽  
Huan-Chieh Chien ◽  
Wenlong Cai ◽  
...  
Keyword(s):  
Drug Absorption ◽  
Azo Dye ◽  
Pharmacokinetic Studies ◽  
Unintended Effects ◽  
Drug Products ◽  
Intestinal Drug Absorption ◽  
High Concentrations ◽  
Gut Microbial Community ◽  
Selection Of

Food and drug products contain diverse and abundant small-molecule additives (excipients) with unclear impacts on human physiology, drug safety, and response. Here, we evaluate their potential impact on intestinal drug absorption. By screening 136 unique compounds for inhibition of the key intestinal transporter OATP2B1 we identified and validated 24 potent OATP2B1 inhibitors, characterized by higher molecular weight and hydrophobicity compared to poor or noninhibitors. OATP2B1 inhibitors were also enriched for dyes, including 8 azo (R−N=N−R′) dyes. Pharmacokinetic studies in mice confirmed that FD&C Red No. 40, a common azo dye excipient and a potent inhibitor of OATP2B1, decreased the plasma level of the OATP2B1 substrate fexofenadine, suggesting that FD&C Red No. 40 has the potential to block drug absorption through OATP2B1 inhibition in vivo. However, the gut microbiomes of multiple unrelated healthy individuals as well as diverse human gut bacterial isolates were capable of inactivating the identified azo dye excipients, producing metabolites that no longer inhibit OATP2B1 transport. These results support a beneficial role for the microbiome in limiting the unintended effects of food and drug additives in the intestine and provide a framework for the data-driven selection of excipients. Furthermore, the ubiquity and genetic diversity of gut bacterial azoreductases coupled to experiments in conventionally raised and gnotobiotic mice suggest that variations in gut microbial community structure may be less important to consider relative to the high concentrations of azo dyes in food products, which have the potential to saturate gut bacterial enzymatic activity.

scholarly journals Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 272
Author(s):  
Arik Dahan ◽  
Isabel González-Álvarez
Keyword(s):  
Drug Absorption ◽  
Unmet Needs ◽  
Drug Formulation ◽  
Fluid Composition ◽  
Mucosal Cell ◽  
Special Issue ◽  
Junction Resistance ◽  
Intestinal Drug Absorption ◽  
Carrier Mediated Transport ◽  
Mechanistic Basis

The gastrointestinal tract (GIT) can be broadly divided into several regions: the stomach, the small intestine (which is subdivided to duodenum, jejunum, and ileum), and the colon. The conditions and environment in each of these segments, and even within the segment, are dependent on many factors, e.g., the surrounding pH, fluid composition, transporters expression, metabolic enzymes activity, tight junction resistance, different morphology along the GIT, variable intestinal mucosal cell differentiation, changes in drug concentration (in cases of carrier-mediated transport), thickness and types of mucus, and resident microflora. Each of these variables, alone or in combination with others, can fundamentally alter the solubility/dissolution, the intestinal permeability, and the overall absorption of various drugs. This is the underlying mechanistic basis of regional-dependent intestinal drug absorption, which has led to many attempts to deliver drugs to specific regions throughout the GIT, aiming to optimize drug absorption, bioavailability, pharmacokinetics, and/or pharmacodynamics. In this Editorial we provide an overview of the Special Issue "Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation". The objective of this Special Issue is to highlight the current progress and to provide an overview of the latest developments in the field of regional-dependent intestinal drug absorption and delivery, as well as pointing out the unmet needs of the field.

scholarly journals Generation of tetracycline-controllable CYP3A4-expressing Caco-2 cells by the piggyBac transposon system

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Moe Ichikawa ◽  
Hiroki Akamine ◽  
Michika Murata ◽  
Sumito Ito ◽  
Kazuo Takayama ◽  
...  
Keyword(s):  
Small Intestine ◽  
Drug Absorption ◽  
Cell Model ◽  
Negative Effects ◽  
Piggybac Transposon ◽  
Drug Metabolizing Enzyme ◽  
Metabolizing Enzyme ◽  
Cyp3a4 Expression

AbstractCaco-2 cells are widely used as an in vitro intestinal epithelial cell model because they can form a monolayer and predict drug absorption with high accuracy. However, Caco-2 cells hardly express cytochrome P450 (CYP), a drug-metabolizing enzyme. It is known that CYP3A4 is the dominant drug-metabolizing enzyme in human small intestine. In this study, we generated CYP3A4-expressing Caco-2 (CYP3A4-Caco-2) cells and attempted to establish a model that can simultaneously evaluate drug absorption and metabolism. CYP3A4-Caco-2 cells were generated by piggyBac transposon vectors. A tetracycline-controllable CYP3A4 expression cassette (tet-on system) was stably transduced into Caco-2 cells, thus regulating the levels of CYP3A4 expression depending on the doxycycline concentration. The CYP3A4 expression levels in CYP3A4-Caco-2 cells cultured in the presence of doxycycline were similar to or higher than those of adult small intestine. The CYP3A4-Caco-2 cells had enough ability to metabolize midazolam, a substrate of CYP3A4. CYP3A4 overexpression had no negative effects on cell proliferation, barrier function, and P-glycoprotein activity in Caco-2 cells. Thus, we succeeded in establishing Caco-2 cells with CYP3A4 metabolizing activity comparable to in vivo human intestinal tissue. This cell line would be useful in pharmaceutical studies as a model that can simultaneously evaluate drug absorption and metabolism.

scholarly journals Drug Disposition in the Lower Gastrointestinal Tract: Targeting and Monitoring

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 161
Author(s):  
Glenn Lemmens ◽  
Arno Van Camp ◽  
Stephanie Kourula ◽  
Tim Vanuytsel ◽  
Patrick Augustijns
Keyword(s):  
Drug Absorption ◽  
Drug Disposition ◽  
Drug Stability ◽  
Ussing Chamber ◽  
Dissolution Kinetics ◽  
Comprehensive Overview ◽  
Drug Molecules ◽  
Epithelial Physiology

The increasing prevalence of colonic diseases calls for a better understanding of the various colonic drug absorption barriers of colon-targeted formulations, and for reliable in vitro tools that accurately predict local drug disposition. In vivo relevant incubation conditions have been shown to better capture the composition of the limited colonic fluid and have resulted in relevant degradation and dissolution kinetics of drugs and formulations. Furthermore, drug hurdles such as efflux transporters and metabolising enzymes, and the presence of mucus and microbiome are slowly integrated into drug stability- and permeation assays. Traditionally, the well characterized Caco-2 cell line and the Ussing chamber technique are used to assess the absorption characteristics of small drug molecules. Recently, various stem cell-derived intestinal systems have emerged, closely mimicking epithelial physiology. Models that can assess microbiome-mediated drug metabolism or enable coculturing of gut microbiome with epithelial cells are also increasingly explored. Here we provide a comprehensive overview of the colonic physiology in relation to drug absorption, and review colon-targeting formulation strategies and in vitro tools to characterize colonic drug disposition.

Design and In-Vivo Evaluation of Risperidone Buccal Mucoadhesive Patches of Interpolymer Matrix

2021 ◽  
pp. 5305-5312
Author(s):  
Pradeep HK ◽  
Girish B ◽  
Nooruddeen K ◽  
Thimmasetty J ◽  
Venkateswarlu BS
Keyword(s):  
Drug Release ◽  
Drug Absorption ◽  
Kinetic Models ◽  
Phosphate Buffer Solution ◽  
Water Soluble ◽  
Content Uniformity ◽  
Human Beings ◽  
Insoluble Polymers

The buccal cavity is an alternate route for the administration of the drug. This route gained acceptance as increase in bioavailability is observed due to bypass of first pass metabolism. Solvent casting method was employed for the preparation of the risperidone mucoadhesive patches using different combinations of water soluble and water insoluble polymers using polyvinyl alcohol as a backing layer. Our main objective of this study was to understand the behaviour of water soluble and water insoluble polymers in combination on release pattern. Six different formulations of mucoadhesive patches were evaluated for physicochemical parameters like weight uniformity, content uniformity, thickness uniformity, surface pH, swelling studies, tensile strength, folding endurance, in-vitro drug release, and in-vivo drug absorption. Drug loaded mucoadhesive patches of various polymer bases had shown 35.64 to 72.33% drug release in 30 min in phosphate buffer solution of pH 6.6. In-vitro release data from patches were fit to different equations and kinetic models to explain release profiles. Kinetic models like Hixon-Crowell and Higuchi models were used. The formulation containing HPMC (15Cps) and polyvinyl pyrrolidone was considered as optimized based on the physicochemical and pharmaceutical properties. In-vivo studies in rabbits, carried out with prior permission from IAEC, showed 80.40% of drug release from the optimized patches. In-vivo and in-vitro correlations were found to be good. The drug absorption was found significant from the optimized formulation in healthy rabbits. The structure of the buccal membrane and permeability factors are similar in both human beings and rabbits. Therefore mucoadhesive patches of risperidone may be accepted with the important advantage of reduced risperidone dose.

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