دورية أكاديمية
Metabolism and disposition of the DOT1L inhibitor, pinometostat (EPZ-5676), in rat, dog and human.
| العنوان: | Metabolism and disposition of the DOT1L inhibitor, pinometostat (EPZ-5676), in rat, dog and human. |
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| المؤلفون: | Waters NJ; Epizyme, Inc., 400 Technology Square, Cambridge, MA, 02139, USA. nwaters95@gmail.com., Smith SA; Epizyme, Inc., 400 Technology Square, Cambridge, MA, 02139, USA., Olhava EJ; Epizyme, Inc., 400 Technology Square, Cambridge, MA, 02139, USA., Duncan KW; Epizyme, Inc., 400 Technology Square, Cambridge, MA, 02139, USA., Burton RD; Quintiles, Indianapolis, IN, 46241, USA., O'Neill J; Charles River Laboratories, Edinburgh, UK., Rodrigue ME; Charles River Laboratories, Montreal, Canada., Pollock RM; Epizyme, Inc., 400 Technology Square, Cambridge, MA, 02139, USA., Moyer MP; Epizyme, Inc., 400 Technology Square, Cambridge, MA, 02139, USA., Chesworth R; Epizyme, Inc., 400 Technology Square, Cambridge, MA, 02139, USA. |
| المصدر: | Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2016 Jan; Vol. 77 (1), pp. 43-62. Date of Electronic Publication: 2015 Dec 08. |
| نوع المنشور: | Clinical Trial, Phase I; Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Springer Verlag Country of Publication: Germany NLM ID: 7806519 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0843 (Electronic) Linking ISSN: 03445704 NLM ISO Abbreviation: Cancer Chemother Pharmacol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Berlin : Springer Verlag Original Publication: Berlin, New York, Springer International. |
| مواضيع طبية MeSH: | Antineoplastic Agents/*pharmacokinetics , Benzimidazoles/*pharmacokinetics , Feces/*chemistry , Methyltransferases/*antagonists & inhibitors, Adult ; Animals ; Antineoplastic Agents/administration & dosage ; Autoradiography/methods ; Benzimidazoles/administration & dosage ; Chromatography, Liquid/methods ; Dogs ; Female ; Histone-Lysine N-Methyltransferase ; Humans ; Infusions, Intravenous ; Male ; Rats ; Rats, Long-Evans ; Rats, Sprague-Dawley ; Species Specificity ; Tandem Mass Spectrometry/methods ; Tissue Distribution |
| مستخلص: | Purpose: 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. Methods: 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. Results: 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. Conclusions: 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. |
| فهرسة مساهمة: | Keywords: DOT1L; Drug disposition; Drug metabolism; Epigenetics; Histone methyltransferase inhibitor; MLL-r leukemia |
| المشرفين على المادة: | 0 (Antineoplastic Agents) 0 (Benzimidazoles) 0 (EPZ-5676) EC 2.1.1.- (DOT1L protein, human) EC 2.1.1.- (Methyltransferases) EC 2.1.1.43 (Histone-Lysine N-Methyltransferase) |
| تواريخ الأحداث: | Date Created: 20151210 Date Completed: 20160517 Latest Revision: 20191210 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1007/s00280-015-2929-y |
| PMID: | 26645404 |
| قاعدة البيانات: | MEDLINE |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 1432-0843 |
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| DOI: | 10.1007/s00280-015-2929-y |