Daily transdermal administration of selegiline to guinea-pigs preferentially inhibits monoamine oxidase activity in brain when compared with intestinal and hepatic tissues
Daily transdermal administration of selegiline to guinea-pigs preferentially inhibits monoamine oxidase activity in brain when compared with intestinal and hepatic tissues
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DOI：
10.1111/j.2042-7158.2003.tb02430.x
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发表时间：
2003-01-01
影响因子：
3.3
通讯作者：
Azzaro, AJ
中科院分区：
文献类型：
--
作者：
Mawhinney, M;Cole, D;Azzaro, AJ
司来吉兰已被配制成丙烯酸聚合物粘合剂混合物，用作每日透皮给药的恒定释放局部贴剂。将该司来吉兰透皮系统（STS）应用于豚鼠，平均释药量为1.185 mg司来吉兰/cm（2）贴剂/24 h。通过改变贴片大小（cm（2））生成STS剂量-反应曲线。确定了一个透皮剂量范围，该剂量范围可抑制豚鼠脑单胺氧化酶-B（MAO-B）超过95%，但对单胺氧化酶-A（MAO-A）活性具有剂量依赖性抑制作用。与十二指肠相比，皮质和纹状体脑区对司来吉兰透皮给药21天每日方案的MAO-A活性抑制的ID 50约低7.5倍;相同给药方案后，肝脏MAO-A未受影响。相比之下，口服司来吉兰对脑和十二指肠MAO-A的抑制程度相同，并且对脑MAO-A抑制产生较浅的剂量-抑制曲线。此外，经皮给药对脑MAO-A活性的抑制作用比口服司来吉兰强约6-8倍。可以得出结论，每日经皮给药司来吉兰可能提供优于口服治疗的治疗优势，基于其优先，剂量依赖性抑制脑与外周MAO-A活性。
Selegiline has been formulated in an acrylic polymer adhesive mixture to be employed as a constant release topical patch for daily transdermal administration. Application of this selegiline transdermal system (STS) to guinea-pigs resulted in an average delivery of 1.185 mg selegiline/cm(2) patch/24 h. STS dose-response curves were generated by altering patch size (cm(2)). A transdermal dose range was identified which inhibited guinea-pig brain monoamine oxiclase-B (MAO-B) by greater than 95 % yet provided for a dose-dependent inhibition of monoamine oxiclase-A (MAO-A) activity. The ID50 for inhibition of MAO-A activity in response to a 21-day daily regimen with transdermal selegiline was approximately 7.5-fold lower for cortical and striatal brain regions compared with that obtained for duodenum; hepatic MAO-A was unaffected following the same dosing regimen. By contrast, orally administered selegiline inhibited brain and duodenal MAO-A to the same extent, and generated a shallower dose-inhibition curve for brain MAO-A inhibition. In addition, transdermal delivery was approximately 6-8-times more potent than oral selegiline for the inhibition of brain MAO-A activity. It is concluded that daily transdermal selegiline administration may provide therapeutic advantages over oral treatment, based on its preferential, dose-dependent inhibition of brain vs peripheral MAO-A activity.