Verapamil metabolism in distinct regions of the heart and in cultures of cardiomyocytes of adult rats

A substantial number of drugs act either directly or indirectly on the hear t, but surprisingly, little is known about drug oxidation in the heart. We therefore investigated the metabolism of the calcium antagonist verapamil i n microsomal fractions isolated from the left and right ventricle of heart muscle and in primary cultures of cardiomyocytes of adult rats. Metabolism of verapamil proceeded predominantly with microsomal fractions isolated fro m the right ventricle of rat heart, and in liquid chromatographic-tandem ma ss spectrometry (LC-MS/MS) and LC-MS3 experiments four metabolites (M1-M4) could be identified. Furthermore, the intermediate biotransformation produc ts M5 to M8 could additionally be identified in cultures of primary cardiom yocytes, thus providing new insight into the mechanisms of the N-dealkylati on and O-demethylation pathway of verapamil. We show metabolism of verapami l to be predominant in the right ventricle of the heart, and the data repor ted herein may explain metabolic inactivation and/or adverse drug reactions of certain cardiovascular drugs on the basis of tissue specific metabolism .