药代动力学研究在新型抗抑郁药E2011中的应用。

Application of pharmacokinetic studies to a novel antidepressant, E2011.

Naitoh T, Horie T, Nagato S, Kagaya T, Kubota A, Akasaka K

Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan.

Xenobiotica. 1994 Aug;24(8):819-26. doi: 10.3109/00498259409043281.

Abstract

The original drug tested here, (5R)-3-[2-(3-cyanopropyl)benzothiazol-6-yl]-5-methoxymethyl-2-oxaz olidinone (ER-4539), exhibited strong MAO-A inhibitory activity in vitro, but its bioavailability in rat was very low. After ER-4539 was administered orally to dog, a metabolite was found in plasma. 2. The metabolite was isolated by hplc after incubation with dog liver microsomal preparations. Its structure, determined by ms and nmr analysis, was alpha-hydroxy-ER-4539. The configuration of the alpha-hydroxy metabolite was (S), determined in comparison with the authentic sample of (R) and (S) by hplc. The isolated metabolite had potent MAO-A inhibitory action in vitro, indicating that it would have antidepressant action. 3. (5R)-3-[2-((1S)-3-Cyano-1-hydroxypropyl)benzothiazol-6-yl]-5- methoxymethyl-2-oxazolidinone (E2011), the synthesized metabolite, has been improved in regard to biopharmaceutical characteristics in rat and dog.

摘要

在此测试的原药，(5R)-3-[2-(3-氰基丙基)苯并噻唑-6-基]-5-甲氧基甲基-2-恶唑烷酮（ER-4539），在体外表现出很强的单胺氧化酶A（MAO-A）抑制活性，但其在大鼠体内的生物利用度非常低。给狗口服ER-4539后，在血浆中发现了一种代谢物。2. 该代谢物在与狗肝微粒体制剂孵育后通过高效液相色谱法（hplc）分离得到。通过质谱（ms）和核磁共振（nmr）分析确定其结构为α-羟基-ER-4539。通过与(R)和(S)的真实样品进行高效液相色谱法比较，确定α-羟基代谢物的构型为(S)。分离得到的代谢物在体外具有有效的MAO-A抑制作用，表明它可能具有抗抑郁作用。3. (5R)-3-[2-((1S)-3-氰基-1-羟基丙基)苯并噻唑-6-基]-5-甲氧基甲基-2-恶唑烷酮（E2011），即合成的代谢物，在大鼠和狗的生物药剂学特性方面有所改善。