Studies on the metabolism of 4-methyl-piperazine-1-carbodithioc acid 3-cyano-3,3-diphenylpropyl ester hydrochloride in rats by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry.
ABSTRACT 4-Methyl-piperazine-1-carbodithioc acid 3-cyano-3,3-diphenylpropyl ester hydrochloride(TM208) is a newly synthesized compound, which has shown excellent in vivo and in vitro anticancer activity and low toxicity. In this study, the metabolism of TM208 in rats was studied for the first time by high-performance liquid chromatography coupled with tandem mass spectrometry. Following a single oral administration to rats, TM208 was metabolized to eight metabolites (M1-M8). M1 is the desmethyl metabolite and the acylation of M1 with N-acetyl transferase results in M6 (N-acetyl metabolite), M5 is N-formyl metabolite; M4 is phenyl monohydroxylation metabolite, M2 is the sulfine metabolite of TM208, and M3 is also an odd-oxygen added products which the possible oxidation site has described in this paper; M8 is the metabolite resulting from the replacement of '-C=S' with '-C=O', M7 is a ring-opened piperazine oxidation products to a kind of acid.
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ABSTRACT: 4-Methyl-piperazine-1-carbodithioc acid 3-cyano-3, 3-diphenylpropyl ester hydrochloride (TM208), a newly synthesized anticancer compound, was quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the first time. A simple, rapid and sensitive assay method using propranolol as internal standard (IS) after one-step precipitation with acetonitrile was developed and validated to determine TM208 in rat plasma. Separation was achieved on a reverse-phase C(18) column with a mobile phase composed of methanol-water (pH4.0) containing 5 m m ammonium acetate in gradient elution mode. A triple quadrupole tandem mass spectrometer with electrospray ionization source was used as detector and operated by multiple reaction monitoring in the positive ion mode. Calibration curves were linear (r > 0.99) between 0.2 and 500 ng/mL. The quantitative limit was 0.2 ng/mL; reliable precision and accuracy were validated by relative standard deviation values in the range 3.44-13.15% and relative error values between -0.58 and -9.78%. The method was successfully applied to preclinical pharmacokinetic studies of TM208.Biomedical Chromatography 12/2011; 26(10):1196-201. · 1.95 Impact Factor