کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
7614931 | 1493980 | 2018 | 8 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Bioanalysis of ibrutinib, and its dihydrodiol- and glutathione cycle metabolites by liquid chromatography-tandem mass spectrometry
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کلمات کلیدی
SMTGSHGSTIMACCGSUHPLCCysBtk - BTKDMSO - DMSOLC-MS/MS - LC-MS / MSMercapturic acid - اسید مرکاپتوریکIbrutinib - ایبوتینیبdHI - بزBruton's tyrosine kinase - تیروزین کیناز BrutonDimethyl sulfoxide - دیمتیل سولفواکسیدLiquid chromatography-tandem mass spectrometry - طیف سنجی جرمی کروماتوگرافی مایع دو طرفهPharmacokinetic(s) - فارماکوکینتیک)MAC - مکPlasma - پلاسماUltra-high-performance liquid chromatography - کروماتوگرافی مایع با کارایی فوق العاده بالاGlu - گلوGlutathione - گلوتاتیونglutathione-S-transferase - گلوتاتیون S-ترانسفراز
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آنالیزی یا شیمی تجزیه
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Ibrutinib is a targeted covalent inhibitor frequently used for the treatment of various lymphomas. In addition to oxidative metabolism, it is metabolized through glutathione coupling. The quantitative insight into this kind of metabolism is scarce, and tools for quantitation are lacking. The non-oxidative metabolism could prove a more prominent role when oxidative metabolism is impaired. Also, in-vitro studies could over-estimate the effect of CYP450-inhibition. To gain quantitative insight into this relatively unknown biotransformation pathway of the drug we have developed a validated simple, fast and sensitive bio-analytical assay for ibrutinib, dihydrodiol-ibrutinib, and the glutathione, cysteinylglycine and cysteine conjugates of ibrutinib in human plasma. The method emphasizes on simplicity, the thiol-conjugates were synthesized by a simple one step synthesis, followed by LC-purification. Sample preparation was done by a simple protein crash with acetonitrile containing labeled internal standards, evaporation of solvents, and reconstitution in eluent. Finally, the compounds were quantified using UHPLC-MS/MS. The assay was successfully validated in a 0.5-500 nM calibration range for all compounds, and also a lower range of 0.05-50â¯nM was demonstrated for ibrutinib to accommodate for even the lowest trough levels. This assay has a considerably higher sensitivity than previous published assays, with the previous lowest LLOQ being 1.14â¯nM. Both, ibrutinib, dihydrodiol-ibrutinib and the cysteine conjugate were deemed stable under refrigerated or frozen storage conditions. At room temperature, the glutathione conjugate showed rapid degradation into the cysteinylglycine conjugate in plasma. Finally, the applicability of the assay was demonstrated in patient samples.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Chromatography B - Volume 1090, 15 July 2018, Pages 14-21
Journal: Journal of Chromatography B - Volume 1090, 15 July 2018, Pages 14-21
نویسندگان
J.J.M. Rood, P.J.A. Dormans, M.J. van Haren, J.H.M. Schellens, J.H. Beijnen, R.W. Sparidans,