Clinical pharmacokinetics of reboxetine, a selective norepinephrine reuptake inhibitor for the treatment of patients with depression

Reboxetine is a novel selective norepinephrine inhibitor that has been eval uated in the treatment of patients with depression. Reboxetine is a racemic mixture, and the (S,S)-(+)-enantiomer appears to be the more potent inhibitor. However, the ratio of the areas under the conce ntration-time curves of the (S,S)-(+)- and (R,R)-(-)-enantiomers in vivo is approximately 0.5. There is no evidence for chiral inversion. Differences in the clearances of the 2 enantiomers may be explained by differences in p rotein binding. The pharmacokinetics of reboxetine are linear following both single and mul tiple oral doses up to a dosage of 12 mg/day, The plasma concentration-time profile following oral administration is best described by a 1-compartment model, and the mean half-life (approximately 12 hours) is consistent with the recommendation to administer the drug twice daily. Reboxetine is well absorbed after oral administration. The absolute bioavai lability is 94.5%, and maximal concentrations are generally achieved within 2 to 4 hours. Food affects the rate, but not the extent, of absorption. Th e distribution of reboxetine appears to be limited to a fraction of the tot al body water due to its extensive (>97%) binding to plasma proteins. The primary route of reboxetine elimination appears to be through hepatic m etabolism. Less than 10% of the dose is cleared renally. A number of metabo lites formed through hepatic oxidation have been identified, but reboxetine is the major circulating species in plasma. III vitro studies show that re boxetine is predominantly metabolised by cytochrome P450 (CYP) 3A4; CYP2D6 is not involved. Reboxetine plasma concentrations are increased in elderly individuals and i n those with hepatic or renal dysfunction, probably because of reduced meta bolic clearance. In these populations, reboxetine should be used with cauti on, and a dosage reduction is indicated. Ketoconazole decreases the clearance of reboxetine, so that the dosage of r eboxetine may need to be reduced when potent inhibitors of CYP3A4 are coadm inistered. Quinidine does not affect the in vitro clearance of reboxetine, confirming the lack of involvement of CYP2D6. There is no pharmacokinetic i nteraction between reboxetine and lorazepam or fluoxetine. Reboxetine at th erapeutic concentrations has no effect on the in vitro activity of CYP1A2, 2C9, 2D6, 2E1 or 3A4. The lack of effect of reboxetine on CYP2D6 and CYP3A4 was confirmed by the lack of effect on the metabolism of dextromethorphan and alprazolam in healthy volunteers. Thus, reboxetine is not likely to aff ect the clearance of other drugs metabolised by CYP isozymes.