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) ( 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 Serial blood samples were withdrawn from the abnormal aorta to assay diltiazem, N-demethyl-diltiazem (MA) and deacetyldiltiazem (M1).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.
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) ( 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 Serial blood samples were withdrawn from the abnormal aorta to assay diltiazem, N-demethyl-diltiazem (MA) and deacetyldiltiazem (M1).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.
Authors: L Pichard; G Gillet; I Fabre; I Dalet-Beluche; C Bonfils; J P Thenot; P Maurel Journal: Drug Metab Dispos Date: 1990 Sep-Oct Impact factor: 3.922