Altered diltiazem metabolism in the neonatal rabbit following intra-uterine chronic exposure to diltiazem

Abstract

1. Diltiazem undergoes extensive metabolism in hepatic and extrahepatic tissues. Deacetyldiltiazem (M1) and N-demethyldiltiazem (MA) are two of the main basic metabolites of diltiazem that retain pharmacological activity. This drug impairs its own metabolism after chronic administration in the adult patient. The study examines the possibility that intra-uterine exposure following chronic maternal therapy with DTZ from mid-gestation to term also impairs DTZ metabolism of its offspring. 2. DTZ was incubated in homogenates from liver, lung, brain and gut and in the whole blood of animals whose mothers were exposed to chronic treatment with diltiazem or unexposed (placebo). DTZ and its metabolites were assayed by HPLC. 3. DTZ deacetylase activity observed in liver, lung and brain homogenates from 1-, 8- and 16-day-old rabbits was significant lower in exposed animals. In gut homogenates, this age-dependent effect was not so clear. This inhibition could not be detected in any organ of 30-day-old rabbits. On the other hand, the activity observed in whole blood was not altered by intra-uterine chronic exposure to DTZ. 4. DTZ demethylase activity showed no differences in tissue homogenates and in whole blood from exposed compared with the unexposed rabbit. 5. In conclusion, the findings suggest that intra-uterine chronic exposure to DTZ has a large and prolonged effect on newborn metabolism deacetylase activity compared with the unexposed rabbit.