High performance liquid chromatography-tandem mass spectrometry method for ex vivo metabolic studies of a rhenium-labeled radiopharmaceutical for liver cancer.

Abstract

The radio-isotope rhenium-labeled N-[2-(triphenylmethyl)thioethyl]-3-aza-19-ethyloxycarbonyl-3-[2-(triphenylmethyl)thioethyl] octadecanoate) ligand (188Re-MN-16ET) is a novel therapeutic agent under preclinical evaluation for hepatoma. A reversed-phase high performance liquid chromatography coupled with a tandem mass spectrometric analysis method and diode array detector (DAD) involving a T type splitter was developed to characterize this pharmaceutical in rat liver tissue solution and determine its biotransformation rate. The separation was accomplished on a C18 column (chromolith silica, 4.6 mm x 100 mm) using an acetonitrile-ammonium acetate buffer gradient as the mobile phase. The detection was achieved by DAD set at 250nm and tandem mass spectrometry using electrospray ionization in the positive ion mode. Re-MN-16ET displayed a retention time of 23.2 min and a transition ion pair corresponding to m/z677 --> 631 for multiple reaction monitoring. Its biotransformation reaction in rat liver homogenate proceeded for 90 min in a 37°C water bath. The characterization was conducted using aliquots that were extracted and concentrated from the reaction mixture for various incubation times. Re-MN-16ET exhibited a biotransformation half-life (t1/2) of 8-9 min in liver tissue solution and was almost completely exhausted after 90 min. Two of its metabolites, consisting of the Re-labeled carboxylic acid derivative, predominately, and its corresponding demetallized disulfide ligand were found in the liver homogenate, providing a metabolism pathway for the radio-pharmaceutical.

• Authors: Wei-Hsi Chen, Chen-Wei Liao, Tsai-Yueh Luo, Yu Chang, Lee-Chung Men, Yi-Cheng Hsieh
• Journal: European journal of mass spectrometry (Chichester, England) (Eur J Mass Spectrom (Chichester)) Vol. 20 Issue 5 Pg. 375-82 ( 2014) ISSN: 1469-0667 [Print] England
• PMID: 25707127 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 188Re-MN-16ET
• Coordination Complexes
• Radioisotopes
• Radiopharmaceuticals
• Rhenium

Topics

• Animals
• Chromatography, High Pressure Liquid (methods)
• Coordination Complexes (analysis, pharmacokinetics, therapeutic use)
• Half-Life
• Liver (drug effects, metabolism)
• Liver Neoplasms (diagnosis, drug therapy)
• Male
• Radioisotopes
• Radiopharmaceuticals (analysis, therapeutic use)
• Rats, Sprague-Dawley
• Rhenium (pharmacokinetics)
• Spectrometry, Mass, Electrospray Ionization (methods)
• Tandem Mass Spectrometry (instrumentation, methods)