کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2478991 1113416 2014 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
CYP-dependent Metabolism of Antitumor Pyrazolo[3,4-d]pyrimidine Derivatives Is Characterized by an Oxidative Dechlorination Reaction
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی اکتشاف دارویی
پیش نمایش صفحه اول مقاله
CYP-dependent Metabolism of Antitumor Pyrazolo[3,4-d]pyrimidine Derivatives Is Characterized by an Oxidative Dechlorination Reaction
چکیده انگلیسی

Summary:The aim of this study is to investigate the metabolic (cytochrome P450-dependent) behaviour of pyrazolo[3,4-d]pyrimidines 1–10 dual Abl/Src kinase inhibitors. All the compounds demonstrate good metabolic stability both in human liver (HLM) and in rat liver (RLM) microsomes. Moreover, all the tested molecules undergo the same metabolic CYP-dependent reactions, namely oxidative dechlorination and N-dealkylation. These metabolic pathways are fully characterized for compound 1 . In HLM, the dehalogenated metabolite accounts for about 87% of the full 1 metabolism, while the N-dealkylated metabolite accounts for 12%. Inhibition studies performed using different CYP-inhibitors indicate that the 3A family is the isoenzyme family most involved in pyrazolo[3,4-d]pyrimidine metabolism. This observation is confirmed by studies performed by using CYP3A selective substrates. Furthermore kinetic analysis performed in RLM, HLM and cDNA CYP3A4 shows that the affinity of CYPs towards compound 1 is similar in all the tested preparations (Km = 32.7, 21.8, and 48.7 μΜ, respectively).

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Drug Metabolism and Pharmacokinetics - Volume 29, Issue 6, 2014, Pages 433–440
نویسندگان
, , , , , , , , , ,