Abstract：
The pharmacokinetics, metabolism, excretion, mass balance, and tissue distribution of [14C]aficamten were evaluated following oral administration of an 8 mg/kg dose in Sprague Dawley rats and in a quantitative whole-body autoradiography study in Long Evans rats.[14C]Aficamten accounted for ∼80% and a hydroxylated metabolite (M1) accounted for ∼12% of total radioactivity in plasma over 48-h (AUC0-48). Plasma tmax was 4-h and the t1/2 of total plasma radioactivity was 5.8-h.Tissues showing highest Cmax exposures were myocardium and semitendinosus muscle.Most [14C]aficamten-derived radioactivity was excreted within 48-h post-administration. Mean cumulative recovery in urine and faeces over 168-h was 8.3% and 90.7%, respectively.In urine and bile, unchanged aficamten was detected at <0.1 and <0.2% of dose, respectively; however, based on total radioactivity excreted in urine (8.0%) and bile (51.7%), approximately 60% of dose was absorbed.[14C]Aficamten was metabolised by hydroxylation with subsequent glucuronidation where the most abundant metabolite recovered in bile was M5 (35.2%), the oxygen-linked glucuronide of hydroxylated aficamten (M1a). The major metabolite detected in faeces was a 1,2,4-oxadiazole moiety ring-cleaved metabolite (M18, 35.3%), shown to be formed from the metabolism of M5 in incubations with rat intestinal contents solution.
摘要：
药代动力学，新陈代谢，排泄,质量平衡,在SpragueDawley大鼠中口服8mg/kg剂量并在LongEvans大鼠中进行定量全身放射自显影研究后，评估了[14C]aficanten的组织分布。[14C]Aficamten占〜80％，羟基化代谢物（M1）占48小时血浆总放射性的〜12％（AUC0-48）。血浆tmax为4小时，总血浆放射性的t1/2为5.8小时。显示最高Cmax暴露的组织是心肌和半腱肌。大多数[14C]aficamten衍生的放射性在给药后48小时内排出。尿液和粪便在168小时内的平均累积回收率分别为8.3%和90.7%，分别。在尿液和胆汁中，在<0.1％和<0.2％的剂量下检测到未改变的非卡定，分别；然而，基于尿液（8.0％）和胆汁（51.7％）中排出的总放射性，大约60%的剂量被吸收。[14C]Aficamten通过羟基化与随后的葡糖醛酸化代谢，其中胆汁中回收的最丰富的代谢物是M5（35.2％），羟基化阿菲卡丁的氧连接葡糖苷酸(M1a)。粪便中检测到的主要代谢产物是1,2,4-恶二唑部分环裂解的代谢产物（M18，35.3%），显示是由与大鼠肠内容物溶液孵育的M5代谢形成的。
