Development of analytical methods for the detarmination of obssity drugs in a small amount of biological samples

(1)建立了芬氟拉明(Fen)及其代谢物去甲氟拉明(Norf)和芬太宁(Phen)等减肥药的高效液相色谱荧光检测方法。在信噪比为3的情况下，这些化合物的最低检测下限为每20μ1注射23fmo1。AUC患者血药浓度升高2.2~2.6倍。同时，Fen浓度不受Phen联合给药的影响。(2)建立了高效液相色谱-荧光检测法测定减肥药马吲哚及其代谢物2-(2-amnoethyl)-3-(p-chlorophenyl)-3-hiydroxyphtalimidine的方法，并将其应用于小鼠脑和血浆样品的分析。在此基础上，建立了测定大鼠毛发中Fen和Norf的高灵敏度方法，并成功地应用于N-亚硝基苯氟胺(N-Fen)对大鼠毛发中Fen和Norf的分析。(3)对健康食品中摄入N-Fen和肝病患者的毛发样品进行了分析。所有被检测的样品都含有Fen和Norf。通过对头发样本的分段分析，阐明了患者长期摄入的原因。(4)苯丙醇胺是一种肥胖剂和鼻卡他药，已被证实会导致脑出血的副作用。因此，它被禁止作为药物使用。为了阐明其不良反应的发生机制，本研究建立了一种高灵敏度的检测方法。咖啡因和氯非那明合用对PPA的药动学参数影响较大，在脑AUC中，咖啡因和氯非那明分别使AUC增加1.6倍和1.5倍。OBdH化合物在AUC中的给药剂量增加1.9倍，两种化合物在AUC中的联合给药比PPA单剂给药增加1.9倍。另一方面，血液中没有观察到显著的差异

(1)A practical HPLC method with fluorescence detection for the determination of bbesity drugs such as fenfluramine(Fen) and its metabolite norfenfluramine(Norf), and phentennine Phen) was developed. The lower detection limits of these compounds were 23 fmol per 20 μ1 injection at a signal-to-noise ratio of 3. Concentration of Phen in brain increased 3.4 times in AUC by co-administration of Fen compared to single dose of Phen. Blood concentration increased 2.2〜2.6 times in AUC. On the other hand, Fen concentration was not influenced by co-administration of Phen.(2)An HPLC-FL method for the determination of an obesity drug mazindole, and its metabolite 2-(2-amnoethyl)-3-(p-chlorophenyl)-3-hiydroxyphtalimidine was developed and applied to their analysis in mouse brain and plasma samples. Further a high sensitive method for the determination of Fen and Norf in rat hair was developed, and successfully applied to their analysis in hair after administration of N-nitrosofenfluramine(N-Fen) to rat.(3)Hair samples of patients who ingested N-Fen in healthy foods and were taken liver disease were analyzed. All the samples determined contained Fen and Norf.. By the segmental analysis of the hair sample, a long ingestion by the patients has been elucidated.(4)Phenylpropanolamine, an obesity and nasal catarrh drug, has been proved to cause side effect of cerebral hemorrhage. As a result, its use as a medicine was prohibited. In this study, to clarify the mechanism of its adverse reaction, a high sensitive determination method was developed. Rharmacokinetic parameters of PPA were fairly influenced by co-administration with caffeine and chlorfeniramine ; 1.6 times increase with caffeine and 1.5 times increase with chlorfeniramine were observed in AUC for brain. OHulministration ofbdh compounds increased 1.9 times in AUC Co-administration of both compounds increased 1.9 times in AUC compared to PPA single dose. On the other hand, no significant difference was observed for blood