希洛班在实验动物和人体中的代谢。

Metabolism of xilobam in laboratory animals and man.

Wu W N, Hills J F, Egan R S

R. W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477.

Xenobiotica. 1994 Jul;24(7):649-62. doi: 10.3109/00498259409043267.

Abstract

Biotransformation and excretion of xilobam (Xm) were studied after single oral doses of Xm-14C in mouse, rat, dog and man. 2. Following oral administration of Xm-14C, recoveries of total 14C (0-24 h) in urine were > or = 78% of the dose in all species. 3. Xm and a total of 11 metabolites have been isolated and identified, which accounted for 30, 65, 21 and 49% of the total 14C in the urine samples from mouse, rat, dog and man, respectively. 4. Xm was sequentially oxidized at the pyrrolidine ring to form 5'-OH Xm and 5'-oxo Xm. Both metabolites were isolated from human plasma accounting for 61% of the radioactivity in the sample. 5'-OH Xm was also identified as a major in vitro metabolite in the 9000g supernatant from a rat liver homogenate preparation. 5. 5'-OH Xm was isolated from the urine of all species except rats. However, oxidation products of 5'-oxo Xm were also present. Oxidation at the phenyl (ph) ring and at the phCH3 group produced the corresponding 4-OHph and phCH2OH metabolites. Subsequent water addition at the 2-position of the pyrrolidine ring followed by cleavage and/or cyclization of the above metabolites resulted in six additional urinary metabolites.

摘要

在小鼠、大鼠、狗和人体中，单次口服含14C标记的西洛巴姆（Xm）后，对其生物转化和排泄情况进行了研究。2. 口服含14C标记的Xm后，所有物种尿液中总14C（0 - 24小时）的回收率均≥剂量的78%。3. 已分离并鉴定出Xm及总共11种代谢物，它们分别占小鼠、大鼠、狗和人体尿液样本中总14C的30%、65%、21%和49%。4. Xm在吡咯烷环上依次氧化形成5'-羟基Xm和5'-氧代Xm。这两种代谢物均从人血浆中分离得到，占样本放射性的61%。5'-羟基Xm也被鉴定为大鼠肝脏匀浆制备物9000g上清液中的主要体外代谢物。5. 除大鼠外，在所有物种的尿液中均分离出了5'-羟基Xm。然而，5'-氧代Xm的氧化产物也存在。苯环（ph）和phCH3基团的氧化产生了相应的4-羟基ph和phCH2OH代谢物。随后在吡咯烷环的2位加水，接着上述代谢物发生裂解和/或环化，又产生了另外六种尿液代谢物。