Metabolism of TM-2, a potential antitumor drug, in rats by using LC-MS.
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.
School of Pharmacy, Shenyang Pharmaceutical University, 103 wenhua Road, Shenyang, 110016, China.
Lei
L
Men
Hongli
H
Lin
Yunli
Y
Zhao
Hui
H
Liu
Mingjing
M
Yang
Ronghua
R
Fan
Pei
P
Wang
Xing
X
Tang
Zhiguo
Z
Yu
D061605:Administration, Intravenous; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000032:analysis* / Q000378:metabolism*; D002853:Chromatography, Liquid; D005260:Female; D008297:Male; D013058:Mass Spectrometry; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043823:Taxoids / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism*
C000593048:13-(N-tert-butoxycarbonyl-3-isobutylisoserinoyl-4,10-diacetoxy-2-benzoyloxy-5-20-epoxy-1,13-dihydroxy-9-oxo-19-norcyclopropa(g)tax-11-ene; D000970:Antineoplastic Agents; D043823:Taxoids
Agents; Antitumor; LC-MS; Metabolism; Orbitrap; Taxane