Disposition of nomifensine after acute and prolonged dosing

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Abstract
The pharmacokinetics of nomifensine were studied after single oral and intravenous doses. The effect of prolonged oral dosing on the pharmacokinetics of nomifensine was also evaluated. Nomifensine was rapidly absorbed from the gastrointestinal tract. The peak concentration of free nomifensine (0.18 .mu.mol/L) was reached at 1.13 hours after dosing. The highest concentration after the intravenous dose was 1.121 .mu.mol/L. The elimination t1/2 after a single dose was about 4 hours regardless of the route of administration. Nomifensine was extensively distributed in body fluids and tissues, with an apparent volume of distribution of 8.69 L/kg. The AUC of free nomifensine after oral dosing was only 26.5% of that after intravenous infusion. Absorption from the gastrointestinal tract was complete, and the AUCs of total nomifensine were equal after all treatments. The main reason for limited bioavailability seems to be extensive first-pass metabolisim during the absorption process. The AUC of free nomifensine decreased substantially (from 0.78 to 0.32 hr .cntdot. .mu.mol/L) and the elimination t1/2 was shortened (from 4.39 to 2.11 hours) after a 2-week dosing period. These effects suggest marked induction of the metabolizing enzymes. An increase in nomifensine dosage may be needed in some patinets to maintain a full therapeutic effect.

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