N-[N-[3-(3-羟基-4-甲氧基苯基)丙基]-α-天冬氨酰]-L-苯丙氨酸 1-甲酯一水合物（安赛蜜）在大鼠、犬和人体内的药代动力学和代谢。

Pharmacokinetics and metabolism of N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame) in the rat, dog, and man.

机构信息

Ajinomoto Pharmaceuticals Co. Ltd., 1-1 Suzuki-cho, Kanagawa Kawasaki-ku, Kawasaki-shi 210-8681, Japan.

出版信息

Food Chem Toxicol. 2011 Nov;49 Suppl 1:S8-29. doi: 10.1016/j.fct.2011.06.042.

DOI:10.1016/j.fct.2011.06.042

PMID:22036030

Abstract

The pharmacokinetics and metabolism of advantame were evaluated in rats, dogs, and humans. The oral pharmacokinetic studies using (14)C-advantame showed that advantame undergoes rapid but incomplete absorption, with an oral bioavailability of total radioactivity in the range of 4-23%. Data indicated that absorption was mainly as ANS9801-acid (de-esterified advantame), which was formed in the gastrointestinal tract as a result of the hydrolysis of the methyl ester group of the parent compound. In the dog, plasma ANS9801-acid was present largely in the form of an unidentified conjugate. Advantame (chiefly in the form of metabolites) was mainly excreted in the feces in rats, dogs, and humans (>80% in each species), with urinary excretion representing a minor route. The predominant metabolite of (14)C-advantame detected in the feces and the urine of rats, dogs, and humans was ANS9801-acid, with lower amounts of 3-[3-hydroxy-4-methoxyphenyl]-1-propylamine (termed HU-1) or N-(3-(3-hydroxy-4-methoxy phenyl))propyl-L-aspartic acid (termed HF-1) present, as well as other minor metabolites and areas of indistinct radioactivity. ANS9801-acid, HU-1, and HF-1 were detected and identified in the urine of rats, humans, and dogs, while ANS9801-acid and HF-1 were identified in the feces of humans and dogs. In the feces of rats, in addition to ANS9801-acid, other additional metabolites were detected, including demethylated ANS9801-acid (designated as RF-1) and another unidentified metabolite (designated as RF-2). Overall, the data show generally similar pharmacokinetics of advantame and ANS9801-acid in animals and in humans and close similarity with neotame. Metabolites of advantame that occur in humans are also found in the 2 species utilized in the toxicology studies, and the metabolism studies support the interpretation of safety data from studies conducted in rats and dogs.

摘要

甜味剂安赛蜜的药代动力学和代谢在大鼠、犬和人体中进行了评估。使用（14）C-安赛蜜的口服药代动力学研究表明，安赛蜜吸收迅速但不完全，总放射性的口服生物利用度在 4-23%范围内。数据表明，吸收主要以 ANS9801-酸（去酯化安赛蜜）的形式存在，这是由于母体化合物的甲酯基团在胃肠道中水解而形成的。在犬中，血浆 ANS9801-酸主要以一种未鉴定的轭合物形式存在。安赛蜜（主要以代谢物形式）主要以粪便形式从大鼠、犬和人体中排泄（在每种物种中>80%），尿液排泄是次要途径。在大鼠、犬和人体的粪便和尿液中检测到的（14）C-安赛蜜的主要代谢物是 ANS9801-酸，其次是 3-[3-羟基-4-甲氧基苯基]-1-丙胺（称为 HU-1）或 N-（3-（3-羟基-4-甲氧基苯基））丙基-L-天冬氨酸（称为 HF-1），以及其他较少的代谢物和放射性不明显区域。在大鼠、犬和人体的尿液中检测到并鉴定了 ANS9801-酸、HU-1 和 HF-1，而在犬和人体的粪便中鉴定了 ANS9801-酸和 HF-1。在大鼠粪便中，除了 ANS9801-酸外，还检测到其他额外的代谢物，包括去甲基 ANS9801-酸（指定为 RF-1）和另一种未鉴定的代谢物（指定为 RF-2）。总的来说，数据表明安赛蜜和 ANS9801-酸在动物和人体中的药代动力学具有一般相似性，与纽甜非常相似。在人类中发现的安赛蜜代谢物也存在于用于毒理学研究的 2 个物种中，代谢研究支持对大鼠和犬研究中安全性数据的解释。