一种新的抗精神病药物齐拉西酮在人体内的代谢和排泄。
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普拉卡什，卡梅尔·A，葛默罗斯·J，威尔纳·K
一种新的抗精神病药物齐拉西酮在人体内的代谢和排泄。
《药物代谢处置》1997七月;25(7):863-72。
- PubMed ID
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9224781 (PubMed视图］
- 摘要
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在四名正常男性志愿者中，研究了一种新的抗精神病药物齐拉西酮的药代动力学、代谢和排泄，在口服单剂量20 mg的14C-和3h标记的齐拉西酮混合物后。在不同的时间间隔收集血液、尿液和粪便，以测定总放射性和代谢谱。在给药11天后，尿液中恢复了20.3 +/- 1%的放射性，粪便中恢复了66.3 +/- 4.8%。齐拉西酮吸收迅速，在给药后2 ~ 6小时出现齐拉西酮及其代谢物的C(max)。未改变药物的平均峰值血药浓度为45 ng/ml，平均AUC(0-t)为335.7 ng x hr/ml。总放射性的平均峰值血清浓度(平均3H和14C)为91 ng-eq/ml，平均AUC(0-t)为724.6 ng-eq x hr/ml。根据AUC(0-t)值，约46%的循环放射性可归因于未改变的药物。齐拉西酮被广泛代谢，只有少量(<给药剂量的5%)作为不变药物随尿液和粪便排出。采用离子喷雾LC/MS和LC/MS/MS同时监测放射性，鉴定了人尿和血清中的12种代谢物。尿液中的主要代谢物为苯吲哚-乙酸及其葡萄糖醛酸缀合物、苄异噻唑-3-基哌嗪(BITP)、BITP-亚砜、BITP-砜及其内酰胺、齐拉西酮-亚砜和与大鼠相似的砜。 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.
