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Studies on optimising the everted gut sac model (EGSM) in rat and possum tissue to compare selective drug movement across the intestinal wall

机译：优化大鼠和负鼠组织内翻肠囊模型（EGSM）以比较选择性药物跨肠壁运动的研究

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摘要

The in-vitro everted gut sac model has been used extensively in the laboratory environment toudinvestigate the transfer of orally administered drugs across the intestinal wall of rodents. Thisudmodel involves excision of fresh tissue from the small intestine, which is then everted andudsectioned into individual sacs and incubated under mammalian physiological conditions inudmedium containing the target drug. One of the limitations of this model is the need to accessudtissue immediately following euthanasia, greatly restricting applicability for many species.udThis study investigated the movement of a number of drugs across the intestinal wall in ratudtissue that had been stored at 4 ºC and then utilised for studies within 60 minutes and afterudbeing stored at 24 h; as well as possum tissue that had been stored for approximately 24 h.udTransfer of the target drugs fluconazole, digoxin and chloramphenicol were significantlyudgreater in the proximal quarter of the small intestine than the distal three, and so this quarterudwas used for remaining experiments. A number of segments could be gained from the lengthudof intestine from this quarter and there was no significant difference shown in transferudbetween any segments.udThe transfer rate of drugs appeared to decrease following the initial 20 minutes of incubation,udand so this initial 20 minutes was investigated in the remaining experiments with rat tissue.udDigoxin, a recognised P-glycoprotein substrate, demonstrated the anticipated lower transferudacross the intestinal wall of the rat compared to fluconazole and chloramphenicol. Whilst theudaddition of 5 μg/mL verapamil increased the initial transfer of digoxin across the gut wall, theudaddition of 25 μg/mL verapamil resulted in significantly lower absorption of all three targetuddrugs following 20 minutes incubation.udThe transfer of glucose following tissue storage for 0.5 hours was slightly significantly lowerudthan the transfer of glucose observed in tissue stored for 24 h.udThe transfer of glucose across the gut wall using possum tissue was investigated at 30, 60 andud90 minutes incubation, however access to fresh tissue was problematic, and the possumudEGSM did not demonstrate the anticipated transfer curve.udThe use of lactate dehydrogenase was examined for use as an indicator of cell toxicity, butudfound to be unreliable.ududThis study concluded that whilst this model may not have future use in wildlife studies thatudare performed ex-situ, sufficient correlations were seen in these experiments to suggestudfurther studies to validate the EGSM using stored tissue would be warranted.
机译：体外翻肠膜囊模型已在实验室环境中广泛用于研究口服给药的药物在啮齿动物肠壁上的转移。该模型包括从小肠切除新鲜组织，然后将其外翻并切成单个囊，并在哺乳动物生理条件下在含有目标药物的培养基中孵育。该模型的局限性之一是在安乐死后需要立即进入输尿管，这极大地限制了许多物种的适用性。 ud这项研究调查了许多药物在大鼠输尿管中通过肠壁运动的情况，该药物已储存在4 ºC，然后在60分钟内用于研究，并在24小时后储存；以及已储存约24 h的负鼠组织。 ud小肠近端四分之一部位的目标药物氟康唑，地高辛和氯霉素的转移明显高于远端三分之一，因此该四分之一部位被用于其余的实验。从这个季度的肠长/ udud可以得到许多片段，并且在任何片段之间的转移 ud都没有显示出显着差异。 ud在开始孵育20分钟后，药物的转移速率似乎降低了，因此在其余的大鼠组织实验中，对最初的20分钟进行了研究。 udDigoxin（一种公认的P-糖蛋白底物）证明，与氟康唑和氯霉素相比，穿过大鼠肠壁的转移预期更低。虽然添加5μg/ mL的维拉帕米会增加地高辛在肠道壁上的初始转移，但是添加25μg/ mL的维拉帕米会导致20分钟孵育后所有三种目标药物的吸收明显降低。组织储存0.5小时后的葡萄糖比在储存24小时的组织中观察到的葡萄糖转移略低。 ud在孵育30、60和ud90分钟后研究了使用负鼠组织穿过肠壁的葡萄糖转移，但是 udEGSM不能证明预期的转移曲线。 ud使用乳酸脱氢酶作为细胞毒性的指标，但是发现不可靠。 ud ud尽管该模型可能无法在非原位进行的野生动植物研究中使用，但在这些实验中看到了足够的相关性，从而建议进一步的研究来验证E使用存储的组织的GSM将得到保证。

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    Kelsall Ashlie Peta;

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  • 年度 2016
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