Gastrointestinal characterisation and drug solubility determination in animals

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

doi:10.1111/jphp.12361

Cited by 14 publications

(10 citation statements)

References 18 publications

(66 reference statements)

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“…Indeed, it is the human postprandial gut that instead features a higher pH value than that of the dog, and is influenced predominantly by food intake . As with the stomach, wide interspecies differences have also been observed in terms of small intestinal pH, and which may readily affect the same parameters of ionizability, solubility, dissolution, and absorption of a drug . For example, pH along the length of the Beagle dog intestine is 1 unit higher than that in humans when normalizing for gastric emptying of a pH‐measuring device .…”

Section: Gi Fluidmentioning

confidence: 99%

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

Hatton

Yadav

Basit

et al. 2015

Journal of Pharmaceutical Sciences

159

110

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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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Section: Gi Fluidmentioning

confidence: 99%

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

Hatton

Yadav

Basit

et al. 2015

Journal of Pharmaceutical Sciences

159

110

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“…In addition, the solubility of ionizable drugs or pH‐responsive formulations is significantly influenced by the differences in pH along the GI tract and interspecies differences (Merchant et al . ).…”

Section: Discussionmentioning

confidence: 97%

Gastrointestinal disorders after immunosuppression: an experimental model to evaluate the influence of monotherapy on motility parameters

Dall'Agnol

Corá

Teixeira

et al. 2017

Experimental Physiology

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What is the central question of this study? The aim was to propose an animal model for investigating the effects of immunosuppressive monotherapy on gastrointestinal motility using a non-invasive biomagnetic technique. What is main finding and its importance? In our experimental study, immunosuppressive drugs currently in use accelerated gastric emptying whilst increasing the frequency and amplitude of gastric contractions after treatment, except for Mycophenolate and azathioprine. Alternating current biosusceptometry is a useful tool to evaluate side-effects of drugs on the gastrointestinal tract, which will help in understanding the symptoms and improving clinical management of patients. The aim was to propose an animal model for investigating the effects of immunosuppressive monotherapy on gastrointestinal motility using a non-invasive biomagnetic technique. Male Wistar rats were randomly distributed into the following treatment groups: ciclosporin, tacrolimus, prednisone, sirolimus, mycophenolate mofetil, everolimus, azathioprine and control. Each animal was treated for 14 days by gavage with dosages ranging from 1 to 20 mg kg day considering the area-to-volume ratio and hepatic metabolism. Gastrointestinal transit and gastric contractility measurements were evaluated by alternating current biosusceptometry before and after treatment. Gastric emptying was faster in animals treated with tacrolimus, prednisone, sirolimus and everolimus compared with control animals (126.7 ± 12.7 min). There was a significant increase in the frequency of contractions after ciclosporin, tacrolimus, azathioprine and sirolimus treatment compared with control animals (4.6 ± 0.3 cycles min ). Increases in the amplitude of contraction were observed after treatment with tacrolimus, sirolimus and everolimus compared with control rats (34.9 ± 6.0 dB). The results showed that our animal model was suitable for demonstrating that most immunosuppressive drugs currently in use impaired at least one gastrointestinal motility parameter. As a non-invasive technique, alternating current biosusceptometry is a potentially useful tool for evaluation of side-effects of drugs in gastrointestinal tract, helping us to understand the symptoms to improve clinical management of patients.

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“…The buffer capacity was found to be 1.4mmol/L/∆pH in dog, and values in human were found to vary from 3.2 to 6.4 mmol/L/∆pH (Kalantzi et al, 2006a;Mudie et al, 2010). In the fed state, the buffer capacity is greater than in the fasted state, but decreases along the gastrointestinal tract in human (30 to 13.2 mmol/L/∆pH) and rat (28.2 to 20.1 mmol/L/∆pH) ( Table 2) (Merchant et al, 2015;Mudie et al, 2010). However, the buffer capacity throughout the fed state dog small intestine is more constant with values of 24-30mmol/L/∆pH (Kalantzi et al, 2006a).…”

Section: Buffer Capacitymentioning

confidence: 96%

“…There are no data regarding the surface tension of the gastric fluids in the fasted state for the rat. In the fed state, surface tension values are close between human and rat (30-31 and 38mN/m, respectively), (Merchant et al, 2015;Mudie et al, 2010;Vertzoni et al, 2007). No data is available regarding the surface tension in fed state in dog.…”

Section: Surface Tensionmentioning

confidence: 97%

“…The osmolality of the fasted state stomach increases from dog to human to rat with values of 74.9mOsm/kg, 171-276mOsm/kg and 290mOsm/kg, respectively (Arndt et al, 2013;Mudie et al, 2010;Pedersen et al, 2013;Pihl et al, 2008). Similarly, the fed state gastric osmolality is higher in rat than in human (794 and 217-559mOsm/kg, respectively) (Merchant et al, 2015;Mudie et al, 2010). There are no data available for the osmolality values for the fed state in dog.…”

Section: Osmolalitymentioning

confidence: 99%

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Considerations for the development of in vitro dissolution tests to reduce or replace preclinical oral absorption studies

Grignard

Taylor

McAllister

et al. 2017

European Journal of Pharmaceutical Sciences

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The pharmaceutical development of new chemical entities can be hampered by their solubility and/or dissolution limitations. Currently, these properties are characterised mostly during in vivo pre-clinical studies. The development of appropriate in vitro methods to study the solubility and dissolution properties in preclinical species would lead to a significant reduction or replacement of the animal experiments at this stage of development. During clinical development, media simulating the human gastrointestinal tract fluids are commonly used and a similar approach mimicking laboratory animals' gastrointestinal tract fluids would impact on the preclinical stage of development. This review summarises the current knowledge regarding the gastrointestinal physiology of the most common laboratory animals, and animal simulated gastric and intestinal media are proposed.

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Gastrointestinal characterisation and drug solubility determination in animals

Cited by 14 publications

References 18 publications

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

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

Gastrointestinal disorders after immunosuppression: an experimental model to evaluate the influence of monotherapy on motility parameters

Considerations for the development of in vitro dissolution tests to reduce or replace preclinical oral absorption studies

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