Waters Nigel J, Smith Sherri A, Olhava Edward J, Duncan Kenneth W, Burton Richard D, O'Neill James, Rodrigue Marie-Eve, Pollock Roy M, Moyer Mikel P, Chesworth Richard
Epizyme, Inc., 400 Technology Square, Cambridge, MA, 02139, USA.
Quintiles, Indianapolis, IN, 46241, USA.
Cancer Chemother Pharmacol. 2016 Jan;77(1):43-62. doi: 10.1007/s00280-015-2929-y. Epub 2015 Dec 8.
The metabolism and disposition of the first-in-class DOT1L inhibitor, EPZ-5676 (pinometostat), was investigated in rat and dog. Metabolite profiles were compared with those from adult patients in the first-in-man phase 1 study as well as the cross-species metabolism observed in vitro.
EPZ-5676 was administered to rat and dog as a 24-h IV infusion of [(14)C]-EPZ-5676 for determination of pharmacokinetics, mass balance, metabolite profiling and biodistribution by quantitative whole-body autoradiography (QWBA). Metabolite profiling and identification was performed by radiometric and LC-MS/MS analysis.
Fecal excretion was the major route of elimination, representing 79 and 81% of the total dose in and rat and dog, respectively. QWBA in rats showed that the radioactivity was well distributed in the body, except for the central nervous system, and the majority of radioactivity was eliminated from most tissues by 168 h. Fecal recovery of dose-related material in bile duct-cannulated animals as well as higher radioactivity concentrations in the wall of the large intestine relative to liver implicated intestinal secretion as well as biliary elimination. EPZ-5676 underwent extensive oxidative metabolism with the major metabolic pathways being hydroxylation of the t-butyl group (EPZ007769) and N-dealkylation of the central nitrogen. Loss of adenine from parent EPZ-5676 (M7) was observed only in rat and dog feces, suggesting the involvement of gut microbiota. In rat and dog, steady-state plasma levels of total radioactivity and parent EPZ-5676 were attained rapidly and maintained through the infusion period before declining rapidly on cessation of dosing. Unchanged EPZ-5676 was the predominant circulating species in rat, dog and man.
The excretory and metabolic pathways for EPZ-5676 were very similar across species. Renal excretion of both parent EPZ-5676 and EPZ-5676-related material was low, and in preclinical species fecal excretion of parent EPZ-5676 and EPZ007769 accounted for the majority of drug-related elimination.
在大鼠和犬体内研究了首个同类DOT1L抑制剂EPZ - 5676（匹诺司他）的代谢和处置情况。将代谢产物谱与首次人体1期研究中成年患者的代谢产物谱以及体外观察到的跨物种代谢情况进行了比较。
以[(14)C]-EPZ - 5676进行24小时静脉输注的方式将EPZ - 5676给予大鼠和犬，通过定量全身放射自显影（QWBA）来测定药代动力学、质量平衡、代谢产物谱和生物分布。通过放射性测定和液相色谱 - 串联质谱（LC - MS/MS）分析进行代谢产物谱分析和鉴定。
粪便排泄是主要的消除途径，分别占大鼠和犬总剂量的79%和81%。大鼠的QWBA显示，除中枢神经系统外，放射性在体内分布良好，到168小时时大部分组织中的放射性已被消除。胆管插管动物粪便中剂量相关物质的回收率以及大肠壁中相对于肝脏更高的放射性浓度表明存在肠道分泌以及胆汁排泄。EPZ - 5676经历了广泛的氧化代谢，主要代谢途径是叔丁基的羟基化（EPZ007769）和中心氮的N - 去烷基化。仅在大鼠和犬的粪便中观察到母体EPZ - 5676（M7）的腺嘌呤丢失，提示肠道微生物群参与其中。在大鼠和犬中，总放射性和母体EPZ - 5676的稳态血浆水平迅速达到，并在输注期间维持，给药停止后迅速下降。未变化的EPZ - 5676是大鼠、犬和人体中主要的循环物质。
EPZ -
