Development of diltiazem deacetylase and demethylase activities during ontogeny in rabbit.
1. Diltiazem (DTZ) undergoes extensive metabolism in hepatic and extrahepatic tissues. Deacetyldiltiazem (M1) and N-desmethyldiltiazem (MA) are two of the main basic metabolites of DTZ that retain pharmacological activity. The development of DTZ deacetylase and demethylase activities through ontogeny 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 enzyme sources. In addition, in vivo studies using a pharmacokinetic approach were carried out to support the in vitro findings. 2. DTZ was incubated with homogenates of selected tissues and in whole blood and DTZ, and its metabolites were assayed by HPLC. In addition, a pharmacokinetic study after intraperitoneal administration of DTZ in the 1-, 8-, 16-, 30-day-old and adult rabbit were also carried out. 3. DTZ deactylase activity was detected whatever the age and tissue examined (including blood). Except in gut homogenates, this activity was shown to be higher at earlier postnatal ages. DTZ demethylase activity was only detected in the liver and gut homogenates and in whole blood. This activity increases 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 ontogeny (except for the 30-day-old rabbit) after DTZ intraperitoneal administration. 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 disposition and, for this reason, dosage may not have to be taken into account as a function of age.
Fraile
L J
LJ
Department of Pharmacology and Physiology, Faculty of Veterinary Science, University of Zaragoza, Spain.
Bregante
M A
MA
Garcia
M A
MA
Solans
C
C
D000367:Age Factors; D000375:Aging; D000818:Animals; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004110:Diltiazem / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D006867:Hydrolases / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008956:Models, Chemical; D015233:Models, Statistical; D010090:Oxidoreductases, O-Demethylating / Q000378:metabolism; D011817:Rabbits; D013997:Time Factors; D014018:Tissue Distribution
D002121:Calcium Channel Blockers; D010090:Oxidoreductases, O-Demethylating; D006867:Hydrolases; D004110:Diltiazem