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Acta Pharmacol Sin. 2004 Jan;25(1):121-8.

In vitro identification of metabolites of verapamil in rat liver microsomes.

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Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University, Shenyang 110016, China.



To investigate the metabolism of verapamil at low concentrations in rat liver microsomes.


Liver microsomes of Wistar rats were prepared using ultracentrifuge method. The in vitro metabolism of verapamil was studied with the rat liver microsomal incubation at concentration of 1.0 micromol/L and 5.0 micromol/L. The metabolites were separated and assayed by liquid chromatography-ion trap mass spectrometry (LC/MSn), and further identified by comparison of their mass spectra and chromatographic behaviors with reference substances.


Eight metabolites, including two novel metabolites (M4 and M8), were found in rat liver microsomal incubates. They were identified as O-demethyl-verapamil isomers (M1-M4), N-dealkylated derivatives of verapamil (M5-M7), and N,O-didemethyl-verapamil (M8).


O-Demethylation and N-dealkylation were the main metabolic pathways of verapamil at low concentrations in rat liver microsomes, and the relative proportion of them in verapamil metabolism changed with different substrate concentrations.

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