First-pass metabolism of diltiazem in anesthetized rabbits: role of extrahepatic organs.
OBJECTIVE
The aim of this study was to assess in vivo which organs contribute to the first-pass metabolism of diltiazem.


METHODS
Anaesthetized rabbits received diltiazem into the thoracic aorta (TA) ( 1mg/kg), jugular vein (JV) (2 mg/kg), portal vein (PV) (4 mg/kg) or small intestine (SI) (5 mg/kg). Serial blood samples were withdrawn from the abnormal aorta to assay diltiazem, N-demethyl-diltiazem (MA) and deacetyldiltiazem (M1).


RESULTS
The area under diltiazem plasma concentration curve/time (AUC0-infinity) normalized by the dose was AUCTA approximately equal to AUCJV > AUCPV > AUCSI: Intestinal and hepatic diltiazem availability was 43 and 33%, respectively. The systemic availability of oral diltiazem was 12%. Diltiazem given into the SI and PV generated primarily MA, and injected into the JV and TA produced mainly M1.


CONCLUSIONS
In rabbits, the intestine and the liver contribute to the first-pass metabolism of diltiazem, and the amount and species of metabolites generated depend upon the route of administration of diltiazem.
Lefebvre
M
M
Département de Pharmacologie, Faculté Médecine, Université de Montréal, Québec, Canada.
Homsy
W
W
Caillé
G
G
du Souich
P
P
D000777:Anesthetics; D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000378:metabolism*; D004110:Diltiazem / Q000378:metabolism*; D007275:Injections, Intravenous; D007421:Intestine, Small / Q000502:physiology*; D008168:Lung / Q000502:physiology*; D008297:Male; D011817:Rabbits
D000777:Anesthetics; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004110:Diltiazem