In situ perfusion in rodents to explore intestinal drug absorption: Challenges and opportunities

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.

Intestinal Absorption Mechanisms of Five Flavonoids from Malus hupehensis (Pamp.) Rehd. Extracts in Situ Single-Pass Intestinal Perfusion and in Vitro Caco-2 Cell Model

“…Such as the best intestinal absorption of quercitrin, phloridzin, and phloretin was jejunum, and the ileum may be the best absorption intestine segment of quercetin. These results were similar to the result of related literatures, those reported that quercetin, from Hippophaë rhamnoides extracts, has the best absorption effect in the ileum [14], and the best absorption intestinal segments of the phloridzin monomer is the jejunum [30]. These results were possibly related to the pK a of the drug, the degree of dissociation, pH of the intestinal uid, the surface area of intestine mucosa, the thickness of mucous layers, the activities of enzyme, the ow rate of capillary blood, the components of membrane, the resistance of tight junction, and the distribution of e ux transporters and uptake transporters in the different intestinal [31,32].…”

“…And the absorption is one of the most important aspects. Generally, orally administered drugs are absorbed from the gastrointestinal tract, and intestinal permeability is considered to be a key determinant of the absorbed dose fraction, which directly affects bioavailability and bioequivalence, and will guide the design of oral drug products [13,14]. But there were no relative researches on the absorption of the Malus hupehensis (Pamp.)…”

“…But there were no relative researches on the absorption of the Malus hupehensis (Pamp.) Rehd.. Until now, many absorption models, such as singlepass intestinal perfusion (SPIP) in situ, intestinal loops, isolated mucosa, and in vitro Caco-2 cell monolayers, everted sacs, are extensively used to investigate the intestinal absorption behavior of drugs [14][15][16]. Compared with other models, SPIP is simple and highly accurate in predicting the properties of intestinal absorption as the result of the intestinal manipulation is minimal, and normal blood supply is maintained [17,18].…”

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

“…A well-documented method to explore the performance of drug delivery systems in situ is the intestinal perfusion technique in rodents, introduced by Schanker in 1958 [29]. Several decades later, the technique is still widely applied in the field of intestinal absorption research due to its versatility [30][31][32]. Furthermore, the in situ technique provides the opportunity to investigate absorption and mucoadhesion simultaneously in a specific region of the intestine.…”

Ex Vivo and In Situ Evaluation of ‘Dispelling-Wind’ Chinese Medicine Herb-Drugs on Intestinal Absorption of Chlorogenic Acid

“…Although there are some advantages of the well‐established everted gut sac model like similarity to an in vivo situation, a relatively large surface area available for absorption and the presence of a mucus layer, the everted gut sac model is unable to provide quantitative data on the absorption kinetics of detailed parameters, and the intestine tissue is easily damaged because of interruptions to local blood flow and interruption of nerves (Luo et al , ). The disadvantages of the everted gut sac model can be remedied by using an in situ single‐pass intestinal perfusion model, which provides intact intestinal mucosa, nerve system and blood flow, together with expression of enzymes as well as transporters (Stappaerts et al , ). Consequently, the combination of using ex vivo everted intestinal sac and in situ single pass perfusion methods are commonly used.…”