First-pass metabolism of diltiazem in anesthetized rabbits: Role of extrahepatic organs

Purpose. 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) (1 mg/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 Serial blood samples were withdrawn from the abdominal aorta to assay diltiazem, N-demethyl-diltiazem (MA) and deacetyldiltiazem (M(1)). Results. The area under diltiazem plasma concentration curve/time (AUG(0-infinity)) normalized by the dose was AUG(TA) approximate to AUG(JV) > AUG(PV) > AUG(SI). 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 M(1). 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.