Abstract
A substantial number of drugs act either directly or indirectly on the heart, but surprisingly, little is known about drug oxidation in the heart. We therefore investigated the metabolism of the calcium antagonist verapamil in 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 from the right ventricle of rat heart, and in liquid chromatographic-tandem mass spectrometry (LC-MS/MS) and LC-MS3 experiments four metabolites (M1–M4) could be identified. Furthermore, the intermediate biotransformation products M5 to M8 could additionally be identified in cultures of primary cardiomyocytes, thus providing new insight into the mechanisms of the N-dealkylation andO-demethylation pathway of verapamil. We show metabolism of verapamil to be predominant in the right ventricle of the heart, and the data reported herein may explain metabolic inactivation and/or adverse drug reactions of certain cardiovascular drugs on the basis of tissue specific metabolism.
Footnotes
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Send reprint requests to: Dr. Jürgen Borlak, Fraunhofer Institute of Toxicology and Aerosol Research, Center of Drug Research and Medical Biotechnology, Nicolai-Fuchs-Str. 1, D-30659 Hannover, Germany. E-mail: Borlak{at}ita.fhg.de
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↵1 Both authors contributed equally to this study.
- Abbreviations used are::
- ACE
- angiotensin-converting enzyme
- CID
- collision-induced dissociation
- P450
- cytochrome P450
- LC-MS
- liquid chromatographic-mass spectrometry
- HPLC-MS
- high-performance liquid chromatography-MS
- FMO
- flavin-containing monooxygenase
- Received November 3, 2000.
- Accepted January 22, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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