Metabolism of TM‐2, a potential antitumor drug, in rats by using LC–MS

Abstract

TM-2 (13-(N-Boc-3-i-butylisoserinoyl-4,10-β-diacetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,13-α-dihydroxy-9-oxo-19-norcyclopropa[g]tax-11-ene) is a novel semisynthetic taxane derivative. Our previous study suggested that TM-2 is a promising antitumor analogue. In this paper, the metabolism of TM-2 was investigated in rats following intravenous administration. Two different types of mass spectrometry-hybrid linear trap quadrupole orbitrap (LTQ-Orbitrap) mass spectrometry and triple-quadrupole tandem (QQQ) mass spectrometry-were employed to acquire structural information of TM-2 metabolites. A total of 17 components were identified as the metabolites of TM-2 in bile, feces, and urine samples. Accurate mass measurement using LC-LTQ-Orbitrap-MS was used to determine the accurate mass data and elemental composition of metabolites thereby confirming the proposed structures of the metabolites. The metabolites proposed were mainly oxidates of TM-2, including methoxy, hydroxyl, dihydroxy, and trihydroxyl analogues. The major metabolic pathway of TM-2 was the hydroxylation of the taxane ring or the lateral chain. These important metabolic data serve as a useful resource to support further research of TM-2.

Approaches, Challenges, and Advances in Metabolism of New Synthetic Cannabinoids and Identification of Optimal Urinary Marker Metabolites

“…6,10,33 High-resolution MS provides accurate mass measurement, efficiently identifying and confirming the SC and fragment ion formulas, and achieving metabolite identification with improved productivity and quality. 29,[33][34][35][36][37] Several nontargeted screening methods were proposed based on liquid chromatography high-resolution MS, providing a robust capability to retrospectively investigate previously acquired data for the presence of new SCs. 6,33,38 Urine is the most common drug-testing matrix because of ample sample volume, high drug concentrations, and especially the longer window of drug detection compared to blood and oral fluid.…”

“…There is a significant effort to develop high‐resolution MS screening methods that are rapid and which may be updated with new drugs more quickly with nontargeted all ion detection to address the constantly changing menu of drugs to be detected . High‐resolution MS provides accurate mass measurement, efficiently identifying and confirming the SC and fragment ion formulas, and achieving metabolite identification with improved productivity and quality . Several nontargeted screening methods were proposed based on liquid chromatography high‐resolution MS, providing a robust capability to retrospectively investigate previously acquired data for the presence of new SCs …”

Application of an LC‐MS/MS method to the pharmacokinetics of TM‐2, a potential antitumour agent, in rats

“…Cytotoxicity was noted especially on cell lines resistant to multiple drug resistance. In vivo , TM‐2 displayed significant activity in nude mice bearing A549 human lung cancer xenografts . Based on its cytotoxic activity, in particular on resistant cancer cell lines, TM‐2 was selected for the subsequent preclinical evaluation.…”

“…As a drug candidate, an early understanding of the pharmacokinetic properties of TM‐2, a potential antitumour agent in animals is a priority. Investigations on the metabolism and the preparation of TM‐2 have already been described . To the best of our knowledge, no reports on the pharmacokinetic study of TM‐2 as well as the analytical method in biological sample are available.…”

“…Investigations on the metabolism and the preparation of TM-2 have already been described. [10,11] To the best of our knowledge, no reports on the pharmacokinetic study of TM-2 as well as the analytical method in biological sample are available. TM-2 belongs to the group of taxanes; several analytical methods based on liquid chromatographytandem mass spectrometry (LC-MS/MS) have been reported for the determination of taxane analogues in biological samples.…”