The influence of AT1002 on the nasal absorption of molecular weight markers and therapeutic agents when co-administered with bioadhesive polymers and an AT1002 antagonist, AT1001.
The influence of AT1002 on the nasal absorption of molecular weight markers and therapeutic agents when co-administered with bioadhesive polymers and an AT1002 antagonist, AT1001.
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当与生物粘附聚合物和 AT1002 拮抗剂 AT1001 共同给药时，AT1002 对分子量标记物和治疗药物的鼻吸收的影响。
DOI：
10.1111/j.2042-7158.2011.01381.x
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Eddington,NatalieD
中科院分区：
文献类型：
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作者：
Song,Keon-Hyoung;Eddington,NatalieD
目的本研究的目的是证明紧密连接渗透增强剂AT1002对分子量标记物和低生物利用度治疗剂的鼻吸收的影响，这些药物与生物粘合剂聚合物或zonulin拮抗剂共给药。方法将AT1002与卡拉胶和Na-CMC配制成生物黏附聚合物，观察AT1002对菊粉、降钙素和沙奎那韦鼻腔吸收的促渗透作用。血液样本在6小时内从颈静脉插管中采集。此外，我们确定了AT1002是否通过激活PAR-2特异性结合一个假定的zonulin受体来发挥渗透增强作用。为了检验这种zonulin拮抗剂AT1001，在AT1002/菊粉溶液给药前30分钟给药，并在6小时内收集血液样本。主要发现生物黏附聚合物并不直接增加菊粉、降钙素和沙奎那韦的吸收，而是促进了AT1002鼻腔给药时的增透作用，从而显著增加了每种药物的吸收。AT1001预处理能拮抗zonulin受体，显著降低AT1002的渗透增强作用。结论这些发现有助于了解AT1002的渗透增强能力及其与受体的结合。此外，AT1002与卡拉胶的结合支持了即使使用生物粘合剂也具有低生物利用度的治疗药物的粘膜递送的发展。
ObjectivesThe purpose of this study was to demonstrate the effects of the tight junction permeation enhancer, AT1002, on the nasal absorption of molecular weight markers and low bioavailable therapeutic agents co-administered with bioadhesive polymers or zonulin antagonist.MethodsThe bioadhesive polymers, carrageenan and Na-CMC, were prepared with AT1002 to examine the permeation-enhancing effect of AT1002 on the nasal absorption of inulin, calcitonin and saquinavir after nasal administration to Sprague–Dawley rats. Blood samples were collected over a 6-hour period from a jugular cannula. In addition, we determined whether AT1002 exerts a permeation-enhancing effect via activation of PAR-2 specific binding to a putative receptor of zonulin. To examine this zonulin antagonist, AT1001, was administered 30 min prior to dosing with an AT1002/inulin solution and blood samples were collected over a 6-hour period.Key findingsThe bioadhesive polymers did not directly increase the absorption of inulin, calcitonin and saquinavir, but promoted the permeation-enhancing effect of AT1002 when delivered nasally, thereby significantly increasing the absorption of each drug. Pre-treatment with AT1001 antagonized the zonulin receptor and significantly minimized the permeation-enhancing effect of AT1002.ConclusionThese findings will assist in understanding the permeation-enhancing capability of and the receptor binding of AT1002. Further, combining AT1002 with carrageenan supports the development of the mucosal delivery of therapeutic agents that have low bioavailability even with bioadhesive agents.