1.Chiral analysis of carvedilol and its metabolites hydroxyphenyl carvedilol and O-desmethyl carvedilol in human plasma by liquid chromatography-tandem mass spectrometry: Application to a clinical pharmacokinetic study.
Nardotto GH1, Coelho EB2, Marques MP1, Lanchote VL3. J Chromatogr B Analyt Technol Biomed Life Sci. 2016 Mar 15;1015-1016:173-80. doi: 10.1016/j.jchromb.2016.02.028. Epub 2016 Feb 23.
Carvedilol is an antihypertensive drug, which is available in clinical practice as a racemic mixture. (S)-(-)-carvedilol is a β- and α1-adrenergic antagonist, while (R)-(+)-carvedilol only acts as an α1-adrenergic antagonist. Carvedilol is metabolized mainly by glucuronidation and, to a lesser extent, by CYP2D6 to hydroxyphenyl carvedilol (OHC) and by CYP2C9 to O-desmethyl carvedilol (DMC). This study describes the development and validation of a method for the sequential analysis of the enantiomers of carvedilol, OHC and DMC in plasma using a Chirobiotic(®) V chiral-phase column coupled to an LC-MS/MS system. The method was linear in the range of 0.05-100, 0.05-10 and 0.02-10ng/mL for the carvedilol, OHC and DMC enantiomers, respectively. Application of the method to the investigation of a patient with type 2 diabetes mellitus treated with a single oral dose of 25mg racemic carvedilol showed plasma accumulation of the (R)-(+)-carvedilol, (R)-(+)-DMC and (R)-(+)-OHC enantiomers.
2.Metabolite profiling of 14C-omacetaxine mepesuccinate in plasma and excreta of cancer patients.
Nijenhuis CM1, Lucas L1, Rosing H1, Robertson P Jr2, Hellriegel ET2, Schellens JH3,4, Beijnen AJ1,4. Xenobiotica. 2016 Mar 21:1-11. [Epub ahead of print]
Omacetaxine mepesuccinate (hereafter referred to as omacetaxine) is a protein translation inhibitor approved by the US Food and Drug Administration for adult patients with chronic myeloid leukemia with resistance and/or intolerance to two or more tyrosine kinase inhibitors. The objective was to investigate the metabolite profile of omacetaxine in plasma, urine and faeces samples collected up to 72 h after a single 1.25-mg/m2 subcutaneous dose of 14C-omacetaxine in cancer patients. High-performance liquid chromatography mass spectrometry (MS) (high resolution) in combination with off-line radioactivity detection was used for metabolite identification. In total, six metabolites of omacetaxine were detected. The reactions represented were mepesuccinate ester hydrolysis, methyl ester hydrolysis, pyrocatechol conversion from the 1,3-dioxole ring. Unchanged omacetaxine was the most prominent omacetaxine-related compound in plasma. In urine, unchanged omacetaxine was also dominant, together with 4'-DMHHT.
3.A phase 1b study of Selumetinib in combination with Cisplatin and Gemcitabine in advanced or metastatic biliary tract cancer: the ABC-04 study.
Bridgewater J1, Lopes A2, Beare S3, Duggan M4, Lee D5, Ricamara M6, McEntee D7, Sukumaran A8, Wasan H9, Valle JW10. BMC Cancer. 2016 Feb 24;16(1):153. doi: 10.1186/s12885-016-2174-8.
BACKGROUND: Combined treatment with cisplatin and gemcitabine (CisGem) is the standard of care for patients with advanced biliary tract cancer (ABC). Selumetinib (AZD6244, ARRY-142886) potently and selectively inhibits MEK1/2, an intracellular kinase and has shown activity in ABC. The objective of the ABC-04 trial was to establish the recommended dose of selumetinib in combination with CisGem in patients with ABC.
4.Quantitative determination of regorafenib and its two major metabolites in human plasma with high-performance liquid chromatography and ultraviolet detection.
Fujita K1, Miura M1, Shibata H2. Biomed Chromatogr. 2016 Apr 2. doi: 10.1002/bmc.3730. [Epub ahead of print]
A simple, highly sensitive and specific high-performance liquid chromatography (HPLC) method was developed for the simultaneous quantitation of regorafenib, N-oxide metabolite (M-2) and the desmethyl N-oxide metabolite (M-5) in human plasma. Regorafenib, M-2 and M-5 and the internal standard sorafenib were separated using a mobile phase of 0.5% KH2 PO4 (pH 3.5)-acetonitrile (30:70, v/v), on a CAPCELL PAK MG II column at a flow rate of 0.5 mL/min and measurement at UV 260 nm. The lower limits of quantification for regorafenib, M-2 and M-5 were 10 ng/mL for each analyte. A procedure using solid-phase extraction required only a small amount of plasma (100 μL) for one analysis while providing high extraction recovery (>81% for all compounds) and good selectivity. Coefficients of variation for intra- and inter-day assays were less than 12.2% for regorafenib, less than 12.3% for M-2 and less than 15.1% for M-5. Accuracies for intra- and inter-day assays were within 9.