Scheinin H, Anttila M, Dahl M L, Karnani H, Nyman L, Taavitsainen P, Pelkonen O, Bertilsson L
Department of Clinical Pharmacology, Karolinska Institute, Huddinge University Hospital, Finland.
Clin Pharmacol Ther. 1998 Oct;64(4):402-11. doi: 10.1016/S0009-9236(98)90071-6.
To determine the possible impact of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of selegiline.
Five poor metabolizers and 8 extensive metabolizers of debrisoquin (INN, debrisoquine) were given 10 mg selegiline hydrochloride. The concentrations of selegiline and its main metabolites in serum were determined for 4 days. The pharmacodynamics were quantitated by measuring platelet monoamine oxidase type B activity for 3 weeks. In addition, the effect of selegiline and its main metabolites on the CYP2D6-catalyzed dextromethorphan O-demethylase activity and the effect of quinidine on the metabolism of selegiline were studied in human liver microsomes.
Peak serum concentrations of selegiline were reached rapidly and ranged from 1 to 32 nmol/L. The metabolite concentrations were considerably higher and remained so for a longer period. There were no significant differences in the pharmacokinetic parameters of selegiline, desmethylselegiline, and l-amphetamine between poor metabolizers and extensive metabolizers. However, the area under the serum concentration-time curve (AUC) values of l-methamphetamine were, on average, 46% higher (P = .01) in poor metabolizers than in extensive metabolizers. No significant correlations were found between debrisoquin metabolic ratio and AUC values of selegiline or its metabolites, except for l-methamphetamine (rs = 0.90; P < .001). The maximum monoamine oxidase type B inhibition was 97% in both groups. The inhibitory potency of selegiline, desmethylselegiline, and l-methamphetamine toward dextromethorphan O-demethylase was very low (50% inhibitory concentration values from 160 to 580 mumol/L). Quinidine (< or = 100 mumol/L) did not inhibit the formation of desmethylselegiline or l-methamphetamine from selegiline.
CYP2D6 is not important in the primary elimination of selegiline, and the biological effect of selegiline seems to be similar in poor metabolizers and extensive metabolizers of debrisoquin. The inhibitory effect of selegiline and its main metabolites on CYP2D6 activity seems to be negligible.
确定细胞色素P450 2D6（CYP2D6）基因多态性对司来吉兰药代动力学和药效学的可能影响。
给予5名异喹胍（国际非专利药品名称，去甲异喹胍）慢代谢者和8名异喹胍快代谢者10 mg盐酸司来吉兰。连续4天测定血清中司来吉兰及其主要代谢产物的浓度。通过测量3周内血小板B型单胺氧化酶活性来定量药效学。此外，在人肝微粒体中研究了司来吉兰及其主要代谢产物对CYP2D6催化的右美沙芬O - 脱甲基酶活性的影响以及奎尼丁对司来吉兰代谢的影响。
司来吉兰血清峰浓度迅速达到，范围为1至32 nmol/L。代谢产物浓度显著更高且持续时间更长。慢代谢者和快代谢者之间司来吉兰、去甲基司来吉兰和l - 苯丙胺的药代动力学参数无显著差异。然而，慢代谢者中l - 甲基苯丙胺的血清浓度 - 时间曲线下面积（AUC）值平均比快代谢者高46%（P = 0.01）。除l - 甲基苯丙胺外（rs = 0.90；P < 0.001），未发现异喹胍代谢率与司来吉兰或其代谢产物的AUC值之间存在显著相关性。两组中最大B型单胺氧化酶抑制率均为97%。司来吉兰、去甲基司来吉兰和l - 甲基苯丙胺对右美沙芬O - 脱甲基酶的抑制效力非常低（50%抑制浓度值为160至580 μmol/L）。奎尼丁（≤100 μmol/L）不抑制司来吉兰去甲基司来吉兰或l - 甲基苯丙胺的形成。
CYP2D6在司来吉兰的主要消除过程中不重要，司来吉兰在异喹胍慢代谢者和快代谢者中的生物学效应似乎相似。司来吉兰及其主要代谢产物对CYP2D6活性的抑制作用似乎可以忽略不计。
