AbstractTo investigate the pharmacokinetics and the disposition of levoprotiline after i.v. and p.o. administration and to assess the absolute bioavailability, 12 healthy volunteers (11 women, 1 man) were given a 10 min i.v. infusion of 15 mg and a p.o. dose of 75 mg in a two‐way crossover study. Blood and urine samples were collected after each dose. Unchanged levoprotiline and the sum of unchanged and glucuronidated levoprotiline (=total levoprotiline) were determined by a specific gas chromatographic‐mass spectrometric method.Intravenous levoprotiline was rapidly and extensively distributed into extravascular sites of the body; the steady‐state volume of distribution was 18·81 kg−1. The elimination of levoprotiline from blood was independent of the dosing route, the half‐life being 18·8h. Only 1·8 and 0·6 per cent of the i.v. and p.o. dose, respectively, were excreted unchanged in the urine, whereas 57 per cent of each dose were renally excreted as total levoprotiline.The absolute bioavailability of p.o. levoprotiline was 40 per cent. About 60 per cent of the dose was subject to a first‐pass effect in the liver. The systemic blood clearance of levoprotiline, determined after i.v. dosing, was 885 ml min−1, the renal blood clearance after i.v. and p.o. dosing was only 16·0 and 14·2 ml min−1, respectively. Presystemic and systemic clearance of levoprotiline occurred predominantly by d
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