کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5823976 | 1118383 | 2011 | 16 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
In vitro liver metabolism of aclidinium bromide in preclinical animal species and humans: Identification of the human enzymes involved in its oxidative metabolism
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کلمات کلیدی
P450ESIFMOCIDbutyrylcholinesteraseSPEPHEMRMBChEm/z - m / zAclidinium bromide - آکیدیینیم برومیدCollision-induced dissociation - اختلاف ناشی از برخوردSolid-phase extraction - استخراج فاز جامدtriethylamine - تری اتیلامینInterspecies differences - تفاوت بین گونه هاHydrolysis rate constant - ثابت سرعت هیدرولیزCytochrome P450 - سیتوکروم پی۴۵۰Enzyme identification - شناسایی آنزیمMass spectrometry - طیف سنجی جرمیphenyl - فنیلIn vitro metabolism - متابولیسم درون بدنMass-to-charge ratio - نسبت جرم به شارژmultiple reaction monitoring - نظارت چندگانه چندگانهTEA - چایliquid chromatography - کروماتوگرافی مایعGlyc - گلیسelectrospray ionization - یونیزاسیون الکترو اسپری
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
داروشناسی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
The metabolism of aclidinium bromide, a novel long-acting antimuscarinic drug for the maintenance treatment of chronic obstructive pulmonary disorder, has been investigated in liver microsomes and hepatocytes of mice, rats, rabbits, dogs, and humans. Due to the rapid hydrolysis of this ester compound, two distinct radiolabeled forms of aclidinium were studied. The main biotransformation route of aclidinium was the hydrolytic cleavage of the ester moiety, resulting in the formation of the alcohol metabolite (M2, LAS34823) and carboxylic acid metabolite (m3, LAS34850), which mainly occurred non-enzymatically. By comparison, the oxidative metabolism was substantially lower and the metabolite profiles were similar across all five species examined. Aclidinium was metabolized oxidatively to four minor primary metabolites that were identified as monohydroxylated derivatives of aclidinium at the phenyl (M4) and glycolyl (m6 and m7) moieties of the molecule. The NADPH-dependent metabolite m4 involved the loss of one of the thiophene rings of aclidinium. Incubations with human recombinant P450 isoforms and inhibition studies with selective chemical inhibitors and antibodies of human P450 enzymes demonstrated that the oxidative metabolism of aclidinium is primarily mediated by CYP3A4 and CYP2D6. Additionally, up to eight secondary metabolites were also characterized, involving further hydrolysis, oxidation, or glucuronidation of the primary metabolites. Also, the liver oxidative metabolism of the alcohol metabolite (LAS34823) resulted in the production of one hydroxylated metabolite (M1) mediated by human CYP2D6, whereas the acid metabolite (LAS34850) was not metabolized enzymatically, although a minor non-enzymatic and NADPH-dependent reduction was observed.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 81, Issue 6, 15 March 2011, Pages 761-776
Journal: Biochemical Pharmacology - Volume 81, Issue 6, 15 March 2011, Pages 761-776
نویسندگان
Joan J. AlbertÃ, Sònia Sentellas, Miquel Salvà ,