Gore A V, Liang A C, Chien Y W
Controlled Drug-Delivery Research Center, Rutgers College of Pharmacy, Piscataway, New Jersey 08854-8067, USA.
J Pharm Sci. 1998 Apr;87(4):441-7. doi: 10.1021/js970359u.
Tacrine (THA), a centrally acting acetylcholine-esterase inhibitor, is presently administered perorally for the treatment of Alzheimer's disease (AD). However, its low bioavailablity (i.e., 17%) and short half-life (2-4 h) demand the search for alternative routes of administration. The primary objective of this study was to assess the potential of absorptive mucosae and skin as routes for improving the systemic delivery of THA. The Yucatan minipig, which has been used increasingly in biomedical research as a useful model for humans, and the domestic pig, which is available at low cost, were evaluated for their suitability as animal model. Permeation kinetics of THA across various absorptive mucosae (nasal, buccal, sublingual, and rectal) of both species of swine were studied in the hydrodynamically well-calibrated Valia-Chien permeation cells. For comparison, permeation through various intestinal segments (duodenum, jejunum, and ileum) was also measured. Results indicated that both species display similar permeation characteristics. However, the data obtained for the domestic pigs shows lower intra- and inter-animal variabilities than that of the Yucatan minipigs. The nasal mucosa was found to have the highest permeability, while the buccal mucosa had the lowest among the absorptive mucosae. The intrinsic permeabilities and diffusivity of THA across the four absorptive mucosae were not significantly different between species but lower than that for the intestinal segments for both species. Using dorsal skin as the model, the skin permeation of THA was also investigated and the results indicated that the domestic swine has a significantly higher skin permeability than the Yucatan minipig, with more than a 2-fold difference in intrinsic permeabilities. The intrinsic permeability, partition coefficient, and diffusivity for domestic pig skin are very similar to that for human cadaver skin. Considering the potential of bypassing the hepatic "first-pass" elimination, the absorptive mucosae may be useful routes for systemic delivery of THA to achieve improved bioavailability. With additional advantages of lower variability, ease of membrane excision, good accessibility, and lower cost, it is concluded that the domestic swine is a better animal model than the Yucatan minipig for preclinical studies on the systemic delivery of tacrine.
他克林（THA）是一种中枢作用的乙酰胆碱酯酶抑制剂，目前通过口服给药来治疗阿尔茨海默病（AD）。然而，其低生物利用度（即17%）和短半衰期（2 - 4小时）促使人们寻找其他给药途径。本研究的主要目的是评估吸收性黏膜和皮肤作为改善THA全身给药途径的潜力。尤卡坦小型猪在生物医学研究中越来越多地被用作人类的有用模型，而成本较低的家猪则被评估其作为动物模型的适用性。在经过流体动力学良好校准的瓦利亚 - 钱氏渗透细胞中，研究了THA在这两种猪的各种吸收性黏膜（鼻、颊、舌下和直肠）中的渗透动力学。为作比较，还测量了THA通过各种肠段（十二指肠、空肠和回肠）的渗透情况。结果表明，这两种猪表现出相似的渗透特性。然而，家猪获得的数据显示，其动物内和动物间的变异性低于尤卡坦小型猪。在吸收性黏膜中，发现鼻黏膜的渗透性最高，而颊黏膜的渗透性最低。THA在这四种吸收性黏膜中的固有渗透率和扩散系数在两种猪之间没有显著差异，但均低于两种猪的肠段。以背部皮肤为模型，还研究了THA的皮肤渗透情况，结果表明家猪的皮肤渗透性明显高于尤卡坦小型猪，固有渗透率相差2倍以上。家猪皮肤的固有渗透率、分配系数和扩散系数与人类尸体皮肤非常相似。考虑到有可能绕过肝脏的“首过”消除，吸收性黏膜可能是实现THA全身给药以提高生物利用度的有用途径。鉴于家猪具有变异性较低、易于切除黏膜、易于操作且成本较低等额外优势，得出结论：在家猪用于他克林全身给药的临床前研究方面，家猪是比尤卡坦小型猪更好的动物模型。
