کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1221815 1494669 2012 5 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
A validated HPLC method with fluorescence detection for the glucuronides of Combretastatin A1 in human plasma, and studies on their cis–trans isomerisation
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آنالیزی یا شیمی تجزیه
پیش نمایش صفحه اول مقاله
A validated HPLC method with fluorescence detection for the glucuronides of Combretastatin A1 in human plasma, and studies on their cis–trans isomerisation
چکیده انگلیسی

Two monoglucuronides (CA1G1 and CA1G2) of the catecholic cis-stilbene Combretastatin A1 (CA1, OXi4500), have been identified in a clinical trial of the bisphosphate prodrug of OXi4500, OXi4503. A validated assay for the two glucuronides in human plasma using HPLC with fluorescence detection after post-column photolysis is described. The assay was linear over the range 25 nM (CA1G1) or 50 nM (CA1G2) – 5000 nM, R2 ≥ 0.996. The intra-day precision for CA1G1 was better than 8.7% RSD (19.4% at the LLOQ), and the inter-day precision was better than 5.5% RSD (7.6% at the LLOQ). The intra- and inter-day accuracies were better than ±12.6% relative error (14.8% at the LLOQ) and 4.8% (5.4% at the LLOQ) respectively. For CA1G2, the intra-day precision was better than 5.7% RSD (7.5% at the LLOQ), and the inter-day precision was better than 4.8% RSD (11.9% at the LLOQ). The intra- and inter-day accuracies were better than ±10.1% relative error (12.6% at the LLOQ) and 2.2% (3.8% at the LLOQ) respectively. Recovery from plasma was measured at three concentrations (125, 625 and 2500 nM). Mean recovery of CA1G1 was 94.5% and ranged from 94.4 to 99.2%. Mean recovery of CA1G2 was 90.7%, range 88–92%.During the validation process, one of the isomers was unexpectedly found to be unstable. CA1G1, substituted ortho to the stilbene, was relatively stable, but the meta-substituted CA1G2 readily converted from the cis-stilbene conformation to the trans isomer. This was catalysed by acid and heavy metals, and could be inhibited by antioxidants such as ascorbic acid. Isomerisation could also be induced by one-electron oxidation processes such as horseradish peroxidase and azide radicals.


► Method for analysis of two glucuronides of OXi4500 (Combretastatin A1) in human plasma validated, using photolytically enhanced fluorescence detection.
► Both metabolites observed in clinical trial of OXi4503 (Combretastatin A1 phosphate), predominantly CA1G1.
► Unexpected cis–trans isomerisation of one positional isomer (CA1G2) observed, catalysed at low pH and inhibited by antioxidants.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical and Biomedical Analysis - Volume 62, 25 March 2012, Pages 114–118
نویسندگان
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