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

The pharmacokinetics of reboxetine, a new antidepressant agent, were found to be close to linear in a crossover study comparing administration of single 2, 3, 4 and 5 mg capsule doses in 15 healthy male volunteers, and in the same study the capsules were bioequivalent to the proposed 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 bioavailability: 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, corresponding to a renal clearance of only 3 mL min(-1) (a value consistent with the rate of glomerular filtration of unbound drug). In vitro, binding to plasma proteins, estimated from radioactivity levels following dialysis of C-14-labelled reboxetine, appeared to be dominated by al-acid glycoprotein without marked saturation up to plasma concentrations of over 500 ng mL(-1) (2.8-3.1% unbound with human plasma from three additional 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).