Tse Susanna, Leung Louis, Raje Sangeeta, Seymour Mark, Shishikura Yoko, Obach R Scott
Pfizer, Inc., Groton, Connecticut (S.T., L.L., R.S.O.), and Collegeville, Pennsylvania (S.R.); Xceleron, Inc., Germantown, Maryland (M.S., Y.S.) and University of Dundee, Scotland, UK (Y.S.)
Pfizer, Inc., Groton, Connecticut (S.T., L.L., R.S.O.), and Collegeville, Pennsylvania (S.R.); Xceleron, Inc., Germantown, Maryland (M.S., Y.S.) and University of Dundee, Scotland, UK (Y.S.).
Drug Metab Dispos. 2014 Dec;42(12):2023-32. doi: 10.1124/dmd.114.059675. Epub 2014 Sep 12.
Cerlapirdine (SAM-531, PF-05212365) is a selective, potent, full antagonist of the 5-hydroxytryptamine 6 (5-HT6) receptor. Cerlapirdine and other 5-HT6 receptor antagonists have been in clinical development for the symptomatic treatment of Alzheimer's disease. A human absorption, distribution, metabolism, and excretion study was conducted to gain further understanding of the metabolism and disposition of cerlapirdine. Because of the low amount of radioactivity administered, total (14)C content and metabolic profiles in plasma, urine, and feces were determined using accelerator mass spectrometry (AMS). After a single, oral 5-mg dose of [(14)C]cerlapirdine (177 nCi), recovery of total (14)C was almost complete, with feces being the major route of elimination of the administered dose, whereas urinary excretion played a lesser role. The extent of absorption was estimated to be at least 70%. Metabolite profiling in pooled plasma samples showed that unchanged cerlapirdine was the major drug-related component in circulation, representing 51% of total (14)C exposure in plasma. One metabolite (M1, desmethylcerlapirdine) was detected in plasma, and represented 9% of the total (14)C exposure. In vitro cytochrome P450 reaction phenotyping studies showed that M1 was formed primarily by CYP2C8 and CYP3A4. In pooled urine samples, three major drug-related peaks were detected, corresponding to cerlapirdine-N-oxide (M3), cerlapirdine, and desmethylcerlapirdine. In feces, cerlapirdine was the major (14)C component excreted, followed by desmethylcerlapirdine. The results of this study demonstrate that the use of the AMS technique enables comprehensive quantitative elucidation of the disposition and metabolic profiles of compounds administered at a low radioactive dose.
塞拉匹定（SAM - 531，PF - 05212365）是一种选择性、强效、5 - 羟色胺6（5 - HT6）受体的完全拮抗剂。塞拉匹定和其他5 - HT6受体拮抗剂已进入临床开发阶段，用于阿尔茨海默病的症状性治疗。进行了一项人体吸收、分布、代谢和排泄研究，以进一步了解塞拉匹定的代谢和处置情况。由于给药的放射性剂量较低，使用加速器质谱（AMS）测定血浆、尿液和粪便中的总（14）C含量和代谢谱。单次口服5毫克剂量的[（14）C]塞拉匹定（177纳居里）后，总（14）C的回收率几乎是完全的，粪便为给药剂量消除的主要途径，而尿液排泄起的作用较小。吸收程度估计至少为70%。合并血浆样本中的代谢物谱分析表明，未变化的塞拉匹定是循环中主要的药物相关成分，占血浆中总（14）C暴露量的51%。在血浆中检测到一种代谢物（M1，去甲基塞拉匹定），占总（14）C暴露量的9%。体外细胞色素P450反应表型研究表明，M1主要由CYP2C8和CYP3A4形成。在合并尿液样本中，检测到三个主要的药物相关峰，分别对应塞拉匹定 - N - 氧化物（M3）、塞拉匹定和去甲基塞拉匹定。在粪便中，塞拉匹定是排泄的主要（14）C成分，其次是去甲基塞拉匹定。本研究结果表明，使用AMS技术能够全面定量阐明低放射性剂量给药化合物的处置和代谢谱。
