Development of diltiazem deacetylase and demethylase activities during ontogeny in rabbit

1. Diltiazem (DTZ) undergoes extensive metabolism in hepatic and extrahepat ic tissues. Deacetyldiltiazem (M1) and N-desmethyldiltiazem (MA) are two of the main basic metabolites of DTZ that retain pharmacological activity. Th e development of DTZ deacetylase and demethylase activities through ontogen y has not been addressed. In order to address this issue, in vitro studies have been carried out using the blood and several tissues of rabbit as enzy me sources. In addition, in vivo studies using a pharmacokinetic approach w ere carried out to support the in vitro findings. 2. DTZ was incubated with homogenates of selected tissues and in whole bloo d and DTZ, and its metabolites were assayed by HPLC. In addition, a pharmac okinetic study after intraperitoneal administration of DTZ in the 1-, 8-, 1 6-, 30-day-old and adult rabbit were also carried out. 3. DTZ deacetylase activity was detected whatever the age and tissue examin ed (including blood). Except in gut homogenates, this activity was shown to be higher at earlier postnatal ages. DTZ demethylase activity was only det ected in the liver and gut homogenates and in whole blood. This activity in creases from the 1- to 30-day-old rabbit (except for blood), after which it decreases slightly to reach the adult level. 4. In vivo experiments showed a close pharmacokinetic profile throughout on togeny (except for the 30-day-old rabbit) after DTZ intraperitoneal adminis tration. 5. Extrahepatic metabolism may play a more significant role in the overall metabolism and pharmacokinetics of DTZ at earlier stages of development. 6. Finally, in vivo studies suggest that age does not seem to modify DTZ di sposition and, for this reason, dosage may not have to be taken into accoun t as a function of age.