In Situ Perfusion Model in Rat Colon for Drug Absorption Studies: Comparison with Small Intestine and Caco-2 Cell Model

Lozoya-Agullo, Isabel; González‐Álvarez, Isabel; González‐Álvarez, Marta; Merino-Sanjuán, Matilde; Bermejo, Marival

doi:10.1002/jps.24447

Cited by 62 publications

(47 citation statements)

References 51 publications

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“…Since the dog is well-known to have a colon that is much more permeable to drugs than that of human, presumably any reference value in human would result in a jejunal vs colonic ratio at least within the same order of magnitude as observed in dog [32]. Consequently, the plasma appearance of these two drugs suggests that the rat SPIP model is unable to accurately predict regional intestinal permeability of medium-to-low permeability drugs in human, which is also reported by others [33]. However, it should be emphasized that the rat SPIP model is still useful for evaluating a range of other biopharmaceutical, physiological, and biochemical processes.…”

Section: Discussionmentioning

confidence: 79%

Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat

et al. 2020

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Sufficient colonic absorption is necessary for all systemically acting drugs in dosage forms that release the drug in the large intestine. Preclinically, colonic absorption is often investigated using the rat single-pass intestinal perfusion model. This model can determine intestinal permeability based on luminal drug disappearance, as well as the effect of permeation enhancers on drug permeability. However, it is uncertain how accurate the rat single-pass intestinal perfusion model predicts regional intestinal permeability and absorption in human. There is also a shortage of systematic in vivo investigations of the direct effect of permeation enhancers in the small and large intestine. In this rat single-pass intestinal perfusion study, the jejunal and colonic permeability of two low permeability drugs (atenolol and enalaprilat) and two high-permeability ones (ketoprofen and metoprolol) was determined based on plasma appearance. These values were compared to already available corresponding human data from a study conducted in our lab. The colonic effect of four permeation enhancers-sodium dodecyl sulfate, chitosan, ethylenediaminetetraacetic acid (EDTA), and caprate-on drug permeability and transport of chromium EDTA (an established clinical marker for intestinal barrier integrity) was determined. There was no difference in jejunal and colonic permeability determined from plasma appearance data of any of the four model drugs. This questions the validity of the rat single-pass intestinal perfusion model for predicting human regional intestinal permeability. It was also shown that the effect of permeation enhancers on drug permeability in the colon was similar to previously reported data from the rat jejunum, whereas the transport of chromium EDTA was significantly higher (p < 0.05) in the colon than in jejunum. Therefore, the use of permeation enhancers for increasing colonic drug permeability has greater risks than potential medical rewards, as indicated by the higher permeation of chromium EDTA compared to the drugs.Pharmaceutics 2020, 12, 242 2 of 14 frequently used in pharmaceutical development to evaluate the potential success of a drug, for instance with oral modified-release (MR) dosage forms. In MR dosage forms, the drug is released throughout the gastrointestinal (GI) tract prior to absorption so the regional intestinal permeability needs to be sufficiently high in both the small and large intestine. The rat and human small intestine have similar drug intestinal absorption profiles and transporter expression patterns, but differ in their enzymatic metabolism [2]. Differences in absorption from the rat and human colon have not been extensively compared, but a recent meta-analysis of rat SPIP data reports regional differences in drug permeability for 42 drugs in this species [3].How relevant for humans are the regional intestinal drug permeability values determined in the rat SPIP model? It is difficult to answer this because of the limited amount of human reference permeability data from the lower GI trac...

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Section: Discussionmentioning

confidence: 79%

Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat

et al. 2020

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“…In rats, the total mucus layer thickness (including the firmly and loosely adherent layers) are respectively 0.480 and 0.829mm at the end of the ileum and in the colon [1]. The colon radius in rats is 0.4cm [25]. Assuming that the rheologic and hydrodynamic parameters are the same in rats, a simple rescaling of our model outcome would give a maximal mucus thickness of 0.272, 0.688 and 0.384mm in the proximal, transverse and distal colon, which is comparable to the rat data.…”

Section: Mucus Layermentioning

confidence: 97%

“…The modeling of the mass transfers through the boundaries is a key step since they account for the lumen-epithelium exchanges, which are central both in the fluid dynamics and in the metabolic activity through metabolite absorption and release. They influence the longitudinal speed, as it will be emphasized in the formula (25) describing the transit motion in Section 2.2. Furthermore, the mass transfers also include the dietary intake, and in particular the fiber intake which is the main source of nutrients for the microbiota.…”

Section: Bacterial Activitymentioning

confidence: 99%

A mathematical model to investigate the key drivers of the biogeography of the colon microbiota

Labarthe

Polizzi

Phan

et al. 2019

Journal of Theoretical Biology

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The gut microbiota, mainly located in the colon, is engaged in a complex dialogue with the large intestinal epithelium through which important regulatory processes for the health and well-being of the host take place. Imbalances of the microbial populations, called dysbiosis, are related to several pathological status, emphasizing the importance of understanding the gut bacterial ecology. Among the ecological drivers of the microbiota, the spatial structure of the colon is of special interest: spatio-temporal mechanisms can lead to the constitution of spatial interactions among the bacterial populations and of environmental niches that impact the overall colonization of the colon. In the present study, we introduce a mathematical model of the colon microbiota in its fluid environment, based on the explicit coupling of a population dynamics model of microbial populations involved in fibre degradation with a fluid dynamics model of the luminal content. This modeling framework is used to study the main drivers of the spatial structure of the microbiota, specially focusing on the dietary fibre inflow, the epithelial motility, the microbial active swimming and viscosity gradients in the digestive track. We found 1) that the viscosity gradients allow the creation of favorable niches in the vicinity of the mucus layer; 2) that very low microbial active swimming in the radial direction is enough to promote bacterial growth, which sheds a new light on microbial motility in the colon and 3) that dietary fibres are the main driver of the spatial structure of the microbiota in the distal bowel whereas epithelial motility is preponderant for the colonization of the proximal colon; in the transverse colon, fibre levels and chemotaxis have the strongest impact on the distribution of the microbial communities.

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“…Both perfusion techniques have shown equally good correlations to literature values of the absorbed fraction of the oral dose (F abs ) in humans [32,33]. The closed-loop in situ perfusion technique based on Doluisio's method [34] has been widely applied for intestinal absorption of different drugs and in different regions of the intestine [35][36][37]. Earlier, the closed-loop intestinal perfusion technique has been applied to investigate the mechanisms governing absorption from drug suspensions [38] and drug-loaded microdevices [16] in the small intestine.…”

Section: Introductionmentioning

confidence: 99%

“…Earlier, the closed-loop intestinal perfusion technique has been applied to investigate the mechanisms governing absorption from drug suspensions [38] and drug-loaded microdevices [16] in the small intestine. The closed-loop perfusion technique has previously been validated to study colonic absorption [37], but has not yet been applied to study mucoadhesion and absorption simultaneously in this region of the GI tract.…”

Section: Introductionmentioning

confidence: 99%

Cubic Microcontainers Improve In Situ Colonic Mucoadhesion and Absorption of Amoxicillin in Rats

Christfort

Guillot²,

Melero³

et al. 2020

Pharmaceutics

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An increased interest in colonic drug delivery has led to a higher focus on the design of delivery devices targeting this part of the gastrointestinal tract. Microcontainers have previously facilitated an increase in oral bioavailability of drugs. The surface texture and shape of microcontainers have proven to influence the mucoadhesion ex vivo. In the present work, these findings were further investigated using an in situ closed-loop perfusion technique in the rat colon, which allowed for simultaneous evaluation of mucoadhesion of the microcontainers as well as drug absorption. Cylindrical, triangular and cubic microcontainers, with the same exterior surface area, were evaluated based on in vitro release, in situ mucoadhesion and in situ absorption of amoxicillin. Additionally, the mucoadhesion of empty cylindrical microcontainers with and without pillars on the top surface was investigated. From the microscopy analysis of the colon sections after the in situ study, it was evident that a significantly higher percentage of cubic microcontainers than cylindrical microcontainers adhered to the intestinal mucus. Furthermore, the absorption rate constants and blood samples indicated that amoxicillin in cubic microcontainers was absorbed more readily than when cylindrical or triangular microcontainers were dosed. This could be due to a higher degree of mucoadhesion for these particular microcontainers.

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In Situ Perfusion Model in Rat Colon for Drug Absorption Studies: Comparison with Small Intestine and Caco-2 Cell Model

Cited by 62 publications

References 51 publications

Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat

Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat

A mathematical model to investigate the key drivers of the biogeography of the colon microbiota

Cubic Microcontainers Improve In Situ Colonic Mucoadhesion and Absorption of Amoxicillin in Rats

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