Pharmacokinetics of toloxatone in man following intravenous and oral administrations.

Pharmacokinetics of the antidepressant drug toloxatone were investigated in man following intravenous and oral administration. Five healthy adult volunteers received a single 1 mg/kg dose given as a gelatin capsule (p.o.) and an i.v. infusion. After p.o. administration toloxatone was rapidly absorbed, peak plasma concentrations (Cmax) ranging from 0.384 to 0.640 mg/l occurred between 0.53 and 1.00 h. Plasma curves were fitted according to a one-compartment open model. After absorption, toloxatone was cleared from plasma with a half-life (t 1/2 beta) of 0.96-1.81 h. Following i.v. administration Cmax values from 0.623 to 0.840 mg/l were reached at the end of the 0.5-h infusion. As observed for the capsule form, the elimination of the drug from the plasma was monophasic with t 1/2 beta of 0.88-2.46 h. Plasma clearance of toloxatone was high (0.462 to 0.860 l/h . kg) and the apparent volume of distribution ranged between 1.09 and 1.64 l/kg. Protein binding to plasma proteins is near 50% and appears almost exclusively due to albumin. Free fatty acids do not modify substantially the degree of binding which is constant over the range of concentrations from 0.05 to 100 mg/l. The availability of the gelatin capsule was 50-62% of the i.v. infusion. Since toloxatone is extensively eliminated in urine as metabolites, the reduced availability of the drug appears to be related mainly to first pass metabolism.