新的抗精神病药物的代谢和排泄,齐拉西酮,在人类身上。
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普拉卡什C,卡迈勒,Gummerus J, K威尔纳
新的抗精神病药物的代谢和排泄,齐拉西酮,在人类身上。
药物金属底座Dispos。1997年7月,25 (7):863 - 72。
- PubMed ID
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9224781 (在PubMed]
- 文摘
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药物动力学、代谢和排泄的新抗精神病药物,齐拉西酮,研究了在四个正常男性志愿者口服后一个20毫克剂量的14 c -和3 h-labeled齐拉西酮的混合物。血液、尿液和粪便收集在不同的时间间隔测定总辐射和代谢。十一天后剂量,20.3 + / - 1%的放射性管理恢复在尿液和粪便中66.3 + / - 4.8%。对齐拉西酮的吸收迅速,C (max)齐拉西酮和代谢物发生在2到6 hr postdose。意味着血清浓度峰值不变药物45 ng / ml,平均AUC (0-t) 335.7 ng x人力资源/毫升。平均总辐射的血清浓度峰值(平均3 h和14 c)是91年ng-eq /毫升,平均AUC (0-t) 724.6 ng-eq x人力资源/毫升。AUC (0-t)值的基础上,大约有46%的循环放射性药物可归因于不变。对齐拉西酮广泛代谢,只有少量(< 5%的服用剂量)尿液和粪便的排泄药物不变。十二个人类尿液和血清代谢物被确定ion-spray LC / MS和LC / MS / MS同时监测放射性物质。尿代谢产物主要是确定为oxindole-acetic酸及其葡糖苷酸共轭benzisothiazole-3-yl-piperazine (BITP) BITP-sulfoxide, BITP-sulfone及其内酰胺,ziprasidone-sulfoxide,砜类似老鼠中确定。 In addition, two novel metabolic pathways (reductive cleavage and N-dearylation of the benzisothiazole ring) were identified for ziprasidone in humans. The metabolites resulted by these pathways were characterized as S-methyl-dihydroziprasidone, S-methyl-dihydro-ziprasidone sulfoxide, and 6-chloro-5-(2-piperazin-1-yl-ethyl)-1,3-dihydro-indol-2-one, respectively. Ziprasidone sulfoxide and sulfone were the major metabolites in human serum. The affinities of the sulfoxide and sulfone metabolites for 5-HT2 and D2 receptors are low with respect to ziprasidone, and are thus unlikely to contribute to its antipsychotic effects. Structures of the major metabolites were confirmed by chromatographic and spectroscopic comparisons to synthetic standards. Based on the structures of these metabolites, four routes of metabolism of ziprasidone were identified: 1) N-dealkylation of the ethyl side chain attached to the piperazinyl nitrogen, 2) oxidation at sulfur resulting in the formation of sulfoxide and sulfone, 3) reductive cleavage of the benzisothiazole moiety, and 4) hydration of the C=N bond and subsequent sulfer oxidation or N-dearylation of the benzisothiazole moiety. The identified metabolites accounted for >90% of total radioactivity recovered in urine.
