Pharmacokinetics of reboxetine in healthy volunteers. Single oral doses, linearity and plasma protein binding

Abstract

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 (tmax approximately 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 approximately equal to 29 mL min-1; Vz/F approximately equal to 32 L); urinary excretion was approximately 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 14C-labelled reboxetine, appeared to be dominated by alpha 1-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 gL-1 orosomucoid alpha 1-acid glycoprotein, and 46.4-47.4% for 40 g L-1 albumin), whilst the mean Cmax in the current study was much lower (164 ng mL-1 after a 5mg dose).

Reboxetine, a selective noradrenaline reuptake inhibitor, is non-sedative and does not impair psychomotor performance in healthy subjects

“…This was clearly seen by the dose-dependent rise in plasma growth hormone levels after reboxetine administration which was not observed following imipramine and placebo administration. This increase with reboxetine dose is consistent with the linear pharmacokinetics of the drug (Edwards et al, 1995).…”

Absolute bioavailability of reboxetine enantiomers and effect of gender on pharmacokinetics

“…Pharmacokinetic studies have shown that the single dose pharmacokinetics of reboxetine are linear through a dose of 5 mg [5] and multiple dose pharmacokinetics are linear through a dose of 2 mg twice daily [6]. Peak concentrations of 111 ng mL − 1 are observed approximately 2 h after administration of a single 4 mg tablet; the terminal elimination half-life is approximately 12-16 h in healthy volunteers [5].…”

“…Peak concentrations of 111 ng mL − 1 are observed approximately 2 h after administration of a single 4 mg tablet; the terminal elimination half-life is approximately 12-16 h in healthy volunteers [5]. Reboxetine is cleared primarily by hepatic metabolism; less than 10% of the dose is excreted in the urine as intact reboxetine [7].…”

Pharmacokinetics of reboxetine in healthy, elderly volunteers

“…The terminal elimination half-life is approximately 13 h. Overall, the pharmacokinetics of reboxetine are linear (4). Reboxetine is cleared primarily by hepatic metabolism, with approximately 9% of the administered dose being excreted unchanged in the urine (4,5).…”

“…Reboxetine is rapidly absorbed in healthy adult subjects, with peak concentrations of 111 ng/ml being observed approximately 2 h after administration of a 4-mg dose (4). The terminal elimination half-life is approximately 13 h. Overall, the pharmacokinetics of reboxetine are linear (4).…”