First-pass metabolism of nomifensine in dogs.

Nomifensine (1 and 5 mg/kg) was administered to dogs orally and intravenously. The pharmacokinetics of the drug was evaluated. Nomifensine was rapidly absorbed from the gastro-intestinal tract reaching maximum concentration at 0.5-1 h. The peak levels were directly proportional to the doses administered. The elimination half-life was 6 h and only very small amounts were found in blood at 24 h after administration. The apparent volume of distribution (Vd) was 120-149 1, suggesting an extensive distribution of the drug throughout body fluids and tissues. The area under the serum concentration-time curve (AUC) obtained after oral administration was significantly smaller than that after intravenous administration indicating incomplete bioavailability of the drug in oral form. The conjugation of nomifensine after the two different administration routes was also studied: the conjugation reaction was in equilibrium at 15 min after oral administration, while after intravenous administration, equilibrium was not reached until 1-1.5 h. The metabolism of nomifensine occurred in the gastrointestinal membranes and or in the liver during the absorption process; the first-pass effect was marked.