Plasma levels of diltiazem, after its chronic administration, are usually higher than predicted. Because several organs contribute to diltiazem metabolism, this study aimed to determine the effect of an infusion of diltiazem to steady state on the ability of the intestine, liver and lungs to metabolize diltiazem and its metabolites N-desmethyldiltiazem (MA) and desacetyldiltiazem (M1). The kinetics of diltiazem were assessed after a single i.v. injection (2 mg/kg) and after an infusion (1.4 mg/kg/hr over 15 hr) of diltiazem. After serial blood sampling, the rabbits were sacrificed, and diltiazem, MA and M1 constant rates of metabolism (Kmet) were estimated in the 10,000 x g supernatants of the intestinal mucosa, liver and lungs. In vivo, the systemic clearance of infused diltiazem was lower than that estimated after i.v. injection of diltiazem, i.e., 54.4 +/- 2.4 vs. 70.3 +/- 5.8 ml/min/kg (P < .05). In vitro, diltiazem Kmet was reduced in liver homogenates from rabbits that had received the infusion of diltiazem, but not in the intestine or lungs. Moreover, the production of MA was reduced in liver homogenates and that of M1 in intestinal and lung homogenates. The Kmet of MA was not affected by the infusion of diltiazem in any tissue studied; however, the Kmet of M1 was reduced by the infusion in the three tissues tested. It is concluded that, in rabbits, long-term administration of diltiazem leads to an accumulation of diltiazem primarily because its N-demethylation is decreased in the liver, in addition, the demethylation of M1 is reduced in the small intestine, liver and lungs.