PHARMACOKINETICS OF REBOXETINE IN HEALTHY-VOLUNTEERS - SINGLE ORAL DOSES, LINEARITY AND PLASMA-PROTEIN BINDING

The pharmacokinetics of reboxetine, a new antidepressant agent, were f ound to be close to linear in a crossover study comparing administrati on of single 2, 3, 4 and 5 mg capsule doses in 15 healthy male volunte ers, and in the same study the capsules were bioequivalent to the prop osed therapeutic tablet formulation (4 mg). Kinetic analysis was based on HPLC assay of reboxetine in plasma and urine collected up to 72 h after each administration. Plasma levels indicated a rapid absorption (t(max) similar or equal to 2 h) and an elimination half-life of about 13 h. Clearance and volume of distribution were modest (ratios to bio availability: CL/F similar or equal to 29 mL min(-1); V-z/F similar or equal to 32 L); urinary excretion was similar to 9% of dose, correspo nding to a renal clearance of only 3 mL min(-1) (a value consistent wi th the rate of glomerular filtration of unbound drug). In vitro, bindi ng to plasma proteins, estimated from radioactivity levels following d ialysis of C-14-labelled reboxetine, appeared to be dominated by al-ac id glycoprotein without marked saturation up to plasma concentrations of over 500 ng mL(-1) (2.8-3.1% unbound with human plasma from three a dditional volunteers; 1.8-2.0% for 2 g L(-1) orosomucoid alpha(1)-acid glycoprotein, and 46.4-47.4% for 40 g L(-1) albumin), whilst the mean C-max in the current study was much lower (164 ng mL(-1) after a 5 mg dose).