Waitzinger J, Ludwig G, Pabst G, Michaelis K, Reh C
L.A.B. GmbH, Neu-Ulm, Germany.
Int J Clin Pharmacol Ther. 1996 Oct;34(10):427-32.
Selegiline, used in the treatment of Parkinson's disease, inhibits the intracerebral degradation of dopamine and the uptake of catecholamines. Due to a high volume of distribution and also a high rate of biotransformation the concentrations of selegiline in plasma are rather low. In addition, there are indications that selegiline binds to erythrocytes. An open, randomized, 2-way cross-over study was performed in 24 healthy male volunteers to determine bioavailability and pharmacokinetic parameters of 2 oral selegiline preparations after single dose administration. Statistical tests were applied to the pharmacokinetic parameters AUCinf, AUC0-8, AUCz, Cmax and tmax. The terminal half-lives t1/2 for selegiline with geometric means of 1.69 h (n = 22) and 1.76 h (n = 21) for treatments A and B and for N-desmethyl-selegiline with geometric means of 1.98 h and 1.96 h for treatments A and B agreed very well. AUCinf of selegiline could be compared between treatments for 14 subjects only. The geometric mean ratio was 97.80% with a 90% confidence interval that ranged from 79.58%-120.17% and thus exceeded the (80%, 125%) range by a very small margin. After correction for the actual dose contained in each of the 2 preparations the geometric mean ratio was calculated to 98.39% with a 90% confidence interval that ranged from 80.06%-120.90% and thus was fully contained within the (80%, 125%) acceptance range. Treatments also agreed very well with respect to AUCinf of N-desmethyl-selegiline, the active metabolite of selegiline, with a geometric mean ratio of 96.14% with a 90% confidence interval that ranged from 92.41%-100.01% so that bioequivalence of the 2 treatments could be shown very clearly with respect to this metabolite. The AUC of N-desmethyl-selegiline in serum is about 6-fold higher than that of the parent drug. It is assessed with low variability. Thus, it is reasonable to base the judgement for or against bioequivalence primarily on the data obtained for the metabolite although "a larger acceptance range may be acceptable if inevitable and clinically acceptable" for the parent compound selegiline which certainly can be classified as a "highly variable compound".
司来吉兰用于治疗帕金森病，可抑制脑内多巴胺的降解及儿茶酚胺的摄取。由于分布容积大且生物转化速率高，司来吉兰在血浆中的浓度相当低。此外，有迹象表明司来吉兰可与红细胞结合。在24名健康男性志愿者中进行了一项开放、随机、双向交叉研究，以确定单次给药后两种口服司来吉兰制剂的生物利用度和药代动力学参数。对药代动力学参数AUCinf、AUC0 - 8、AUCz、Cmax和tmax进行了统计检验。司来吉兰的终末半衰期t1/2，治疗A和治疗B的几何均值分别为1.69小时（n = 22）和1.76小时（n = 21）；N - 去甲基司来吉兰的终末半衰期t1/2，治疗A和治疗B的几何均值分别为1.98小时和1.96小时，两者非常吻合。仅14名受试者的司来吉兰AUCinf可在两种治疗之间进行比较。几何均值比为97.80%，90%置信区间为79.58% - 120.17%，因此仅以非常小的幅度超出了（80%，125%）范围。在对两种制剂中实际含有的剂量进行校正后，计算得出几何均值比为98.39%，90%置信区间为80.06% - 120.90%，因此完全在（80%，125%）接受范围内。两种治疗在司来吉兰的活性代谢产物N - 去甲基司来吉兰的AUCinf方面也非常吻合，几何均值比为96.14%，90%置信区间为92.41% - 100.01%，因此就该代谢产物而言，两种治疗的生物等效性非常明显。血清中N - 去甲基司来吉兰的AUC约为母体药物的6倍。其变异性较低。因此，主要根据代谢产物获得的数据来判断生物等效性是合理的，尽管对于肯定可归类为“高变异化合物”的母体化合物司来吉兰，“如果不可避免且临床上可接受，可能可以接受更大的接受范围”。
