Duncan J D, Hallström G, Paulsen-Sörman U, Lindeke B, Cho A K
Drug Metab Dispos. 1983 Jan-Feb;11(1):15-20.
The effects of methyl, ethyl, isopropyl, isobutyl, and benzyl substituents at the alpha-carbon of N-methyl-2-phenethylamine on the kinetics of its N-demethylation in liver microsomes from both control and phenobarbital pretreated rats were studied. In control microsomes, the kinetic studies indicated that more than one enzyme was active for N-demethylation of N-methyl-alpha-methylphenethylamine (methamphetamine) while the other N-methyl-2-phenethylamines appeared to be demethylated by a single enzyme. In microsomes from phenobarbital pretreated animals, there appeared to be more than one enzyme system which was active for N-demethylation of all compounds except N-methyl-alpha-benzylphenethylamine. One of these had a much higher affinity for alpha-ethyl, isopropyl, and isobutyl N-methylphenethylamines while another exhibited affinities for substrates similar to the constitutive enzyme in control microsomes. A correlation was observed between the octanol-buffer or heptane-buffer distribution ratios of the compounds and the negative logarithm of the Michaelis constant (pKm) for the enzyme in control microsomes and for each of the enzyme systems in microsomes from phenobarbital-pretreated animals. Therefore, it is indicated that the concentration of a substrate at the active site of these microsomal enzymes is a function of its lipid solubility.
研究了 N-甲基-2-苯乙胺α-碳上的甲基、乙基、异丙基、异丁基和苄基取代基对正常大鼠和苯巴比妥预处理大鼠肝脏微粒体中 N-甲基-2-苯乙胺 N-去甲基化动力学的影响。在正常微粒体中，动力学研究表明，对于 N-甲基-α-甲基苯乙胺（甲基苯丙胺）的 N-去甲基化，有不止一种酶具有活性，而其他 N-甲基-2-苯乙胺似乎由单一酶进行去甲基化。在苯巴比妥预处理动物的微粒体中，对于除 N-甲基-α-苄基苯乙胺之外的所有化合物的 N-去甲基化，似乎有不止一种酶系统具有活性。其中一种酶系统对α-乙基、异丙基和异丁基 N-甲基苯乙胺具有更高的亲和力，而另一种酶系统对底物的亲和力与正常微粒体中的组成酶相似。观察到这些化合物在正辛醇-缓冲液或庚烷-缓冲液中的分配比与正常微粒体中酶以及苯巴比妥预处理动物微粒体中各酶系统的米氏常数的负对数（pKm）之间存在相关性。因此，表明这些微粒体酶活性位点处底物的浓度是其脂溶性的函数。
