کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1223316 967887 2010 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Characterisation and identification of the human N+-glucuronide metabolite of cediranib
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آنالیزی یا شیمی تجزیه
پیش نمایش صفحه اول مقاله
Characterisation and identification of the human N+-glucuronide metabolite of cediranib
چکیده انگلیسی

Cediranib (4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline; RECENTIN™), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) of all three VEGF receptors, is currently in Phase III clinical trials for the first-line treatment of colorectal cancer and the treatment of recurrent glioblastoma.During its clinical development a unique human metabolite, an N+-glucuronide, was identified as a major circulating metabolite and one of the major metabolites excreted into faeces. Given the possibility of four sites for the conjugation of the glucuronic acid moiety, determination of the location of the conjugation site on cediranib was warranted. A small quantity of the N+-glucuronide metabolite of cediranib was initially generated using recombinant human uridine glucuronosyltransferase 1A4 (UGT1A4) enzymes. The metabolite generated was characterised by HPLC-UV and mass spectrometric (HPLC–MSn) detection and confirmed by 1H NMR spectroscopy. However, the exact site of conjugation could not be determined without generating more of the metabolite. Hence a subsequent biosynthetic scale-up experiment was devised to generate a sufficiently large quantity for full structural characterisation by 1H NMR spectroscopy.The identity of the N+-glucuronide metabolite generated in the UGT1A4 scale-up experiment was confirmed by HPLC–MSn and displayed the same retention time, molecular mass and mass fragmentation data as the metabolite generated in previous human liver microsomal and hepatocyte incubations.1H NMR spectroscopy clearly showed the characteristic anomeric doublet at approximately 4.7 ppm, which, following irradiation during selective Rotating frame Overhauser Effect Spectroscopy (ROESY) experiments, enabled the site of glucuronidation to be confirmed on the pyrrolidine nitrogen.With the exception of the N+-glucuronide metabolite, all other human metabolites of cediranib were observed following incubation with hepatocytes from rat and cynomolgus monkey, the species used for toxicology testing of the drug [6]. As the N+-glucuronide was not detected in the preclinical species, it is suggested that its formation is more likely in human and higher primates (great apes), a finding widely supported in the literature.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical and Biomedical Analysis - Volume 53, Issue 3, 2 November 2010, Pages 526–536
نویسندگان
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