Influence of ageing on the gastrointestinal environment of the rat and its implications for drug delivery

Merchant, Hamid A.; Rabbie, Sarit C.; Varum, Felipe; Afonso-Pereira, Francisco; Basit, Abdul W.

doi:10.1016/j.ejps.2014.05.004

Cited by 21 publications

(32 citation statements)

References 45 publications

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“…Both substances are reported to be present in rat bile fluids and thus have physiological relevance [18]. Surface tension values obtained for rSIF are in line with recent data [19]. Bile salt and phospholipid concentrations are slightly above values referenced and used for example in GastroPlus models and other references [17].…”

Section: Simulated Rat Intestinal Fluidsupporting

confidence: 71%

See 1 more Smart Citation

Simulated rat intestinal fluid improves oral exposure prediction for poorly soluble compounds over a wide dose range

Berghausen

Seiler²,

Gobeau³

et al. 2016

ADMET DMPK

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Section: Simulated Rat Intestinal Fluidsupporting

confidence: 71%

“…The values for buffer capacity were estimated taking into account human FaSSIF-V2 and the constant bile flow, as there was no reference available at the time of rSIF development. Recent data from Merchant [19] indicate that this value appears to be too low.…”

Section: Simulated Rat Intestinal Fluidmentioning

confidence: 96%

Simulated rat intestinal fluid improves oral exposure prediction for poorly soluble compounds over a wide dose range

Berghausen

Seiler²,

Gobeau³

et al. 2016

ADMET DMPK

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“…On the contrary, selection of an appropriate animal model to evaluate performance of pH‐responsive polymethacrylate polymers (e.g., Eudragit S and FS) dissolving at neutral pH 7.0 and which are water insoluble at lower pH values would necessitate ruling out those rodents that demonstrate consistently low intestinal pH values (<7.0), as highlighted in one of our previous studies . Higher intestinal pH values up to pH 7.4 have been observed in older rats (>38 weeks), however, indicating that they may be more useful for modeling GI pH in place of typically used younger (∼12 weeks) rats …”

Section: Gi Fluidmentioning

confidence: 91%

Animal Farm: Considerations in Animal Gastrointestinal Physiology and Relevance to Drug Delivery in Humans

Hatton

Yadav

Basit

et al. 2015

Journal of Pharmaceutical Sciences

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167

120

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"All animals are equal, but some are more equal than others" was the illustrious quote derived from British writer George Orwell's famed work, Animal Farm. Extending beyond the remit of political allegory, however, this statement would appear to hold true for the selection of appropriate animal models to simulate human physiology in preclinical studies. There remain definite gaps in our current knowledge with respect to animal physiology, notably those of intra- and inter-species differences in gastrointestinal (GI) function, which may affect oral drug delivery and absorption. Factors such as cost and availability have often influenced the choice of animal species without clear justification for their similarity to humans, and lack of standardization in techniques employed in past studies using various animals may also have contributed to the generation of contradictory results. As it stands, attempts to identify a single animal species as appropriately representative of human physiology and which may able to adequately simulate human in vivo conditions are limited. In this review, we have compiled and critically reviewed data from numerous studies of GI anatomy and physiology of various animal species commonly used in drug delivery modeling, commenting on the appropriateness of these animals for in vivo comparison and extrapolation to humans.

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“…The intestinal segments were immediately placed in pre-warmed (37°C) Krebs phosphate buffer (1.2 mM magnesium sulfate, 1.3 mM calcium chloride, 4.8 mM potassium chloride, 16.5 dibasic sodium phosphate, 120.8 mM sodium chloride, adjusted to pH 7.0 with hydrochloric acid) and carefully everted using a glass rod, and the outer connective tissue and inner food debris were removed by careful stripping. The everted intestinal rings were kept in 37°C Krebs phosphate buffer containing exenatide at different concentrations (25,50, 100 µg/mL). At specified time intervals after the addition of peptide, 100 µL aliquots were taken from the incubated solution, centrifuged and diluted with an equal volume of ice-cold 1 M perchloric acid to stop the enzymatic degradation.…”

Section: Peptide Degradation With Everted Intestinal Ringsmentioning

confidence: 99%

“…25,26) Generally, gastric pH tends to be acidic, whereas pH in the distal small intestine is slightly alkaline. The changes in gastrointestinal pH may affect peptide solubility and stability, which in turn influences its bioavailability.…”

Section: Effects Of Ph On Exenatide Stabilitymentioning

confidence: 99%

An Investigation into the Gastrointestinal Stability of Exenatide in the Presence of Pure Enzymes, Everted Intestinal Rings and Intestinal Homogenates

Sun

Wang

Sun

et al. 2016

Biological & Pharmaceutical Bulletin

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The purpose of this study was to investigate the gastrointestinal stability of exenatide to determine the key factor(s) contributing to peptide degradation during the oral delivery process. The effects of pH and various digestive enzymes on the degradation kinetics of exenatide were determined. Moreover, the degradation clearances of peptide were also examined using rat everted intestinal rings and intestinal homogenates from various intestinal locations. Exenatide was comparatively stable within a pH range of 1.2-8. However, obvious degradation was observed in the presence of digestive enzymes. The order of enzymes, in terms of ability to degradate exenatide, was chymotrypsin>aminopeptidase N>carboxypeptidase A>trypsin>pepsin. Chymotrypsin showed the greatest ability to degrade exenatide (half-life t 1/2 , 5.784 10 2 h), whereas aminopeptidase N and carboxylpeptidase A gave t 1/2 values of 3.53 and 10.16 h, respectively. The degradation of exenatide was found to be peptide concentration-and intestinal site-dependent, with a lower clearance in the upper part of the duodenum and the lower part of the ileum. When using intestinal homogenates as enzyme sources, the order, in terms of peptide degradation ability, was ileum>jejunum>duodenum. However, no significant difference was observed in the remaining peptide concentrations throughout 2 h of incubation, which may be due to the involvement of cytosolic enzymes. These results revealed key factors contributing to peptide degradation, and suggest that the inhibition of chymotrypsin and site-specific delivery of exenatide might be advantageous in overcoming metabolic obstacles during its oral delivery.Key words exendin-4; enzymatic degradation; gastrointestinal stability; kinetics Exenatide is a synthetic 39-amino-acid peptide amide with the same amino acid sequence as exendin-4 which was originally isolated from lizard venom, and the sequence of exenatide is shown in Fig. 1. 1) It bears a 53% structural homology to glucagon-like peptide-1 (GLP-1) and can be used as a GLP-1 receptor agonist.2) In comparison with GLP-1, exenatide has a longer half-life due to its resistance to dipeptidyl peptidase IV degradation, and is mainly degraded and eliminated in the kidney after absorption into the systemic circulation.3) Exenatide was approved by the U.S. Food and Drug Administration (FDA) for the treatment of type 2 diabetes in 2005.4) Generally, the medication is administrated subcutaneously twice daily. More recently in 2012, exenatide-loaded extended-release microspheres were approved by the FDA, which allowed it to be injected once a week for the treatment of type 2 diabetes. Although this long-acting medication can significantly reduce the frequency of injections, the therapeutic application of exenatide is still limited due to patient noncompliance related to both the expense associated with injection and pain at the site of injection. Therefore, non-injection routes of administration for exenatide have been the focus of attention over the past several years.5-10) Among...

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Influence of ageing on the gastrointestinal environment of the rat and its implications for drug delivery

Cited by 21 publications

References 45 publications

Simulated rat intestinal fluid improves oral exposure prediction for poorly soluble compounds over a wide dose range

Simulated rat intestinal fluid improves oral exposure prediction for poorly soluble compounds over a wide dose range

Animal Farm: Considerations in Animal Gastrointestinal Physiology and Relevance to Drug Delivery in Humans

An Investigation into the Gastrointestinal Stability of Exenatide in the Presence of Pure Enzymes, Everted Intestinal Rings and Intestinal Homogenates

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