Springer Online Journal Archives 1860-2000
Chemistry and Pharmacology
Abstract Diltiazem (DTZ) is a calcium channel blocker widely used in the treatment of angina and hypertension. DTZ undergoes extensive metabolism yielding several metabolites, some of which are active like N-desmethyldiltiazem (MA), desacetyldiltiazem (M1) and N-desmethyl,desacetyldiltiazem (M2). Due to the nature of its biotransformation, several organs should have the ability to metabolize DTZ, however it is still assumed that the liver is the only organ implicated in its elimination. In this study, the fate of DTZ, MA and M1 was assessed in several organs that could contribute to their biotransformation. To this purpose, DTZ (48.2 µM) was incubated in the 10,000 × g supernatant of homogenates of rabbit tissues for 60 min at 37°C. Multiple samples were withdrawn, and DTZ and its metabolites were assayed by HPLC. The elimination rate constant of DTZ in 10,000 × g supernatants varied between the organs: liver 334 ± 45, proximal small intestine 69 ± 11, distal small intestine 25 ± 3, lungs 15 ± 6 and kidneys 8 ± 6 (10−4 min−1). The metabolism of DTZ in the liver generated large amounts of MA but no M1, and in the small intestine, modest amounts of both metabolites. When MA (50.0 µM) or M1 (53.7 µM) were incubated in liver homogenates, the estimated elimination rate constant were 166 ± 23 and 468 ± 53 (10−4 min−1), respectively. The rate of degradation of the metabolites in the small intestine was much slower. These results demonstrate that, in vitro, DTZ is metabolized by several organs, the liver accounting for 75% of the total activity, and that MA is the major metabolite generated.
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