Pharmacokinetics and metabolism of reboxetine

Reboxetine is a novel selective noradrenaline inhibitor developed as an ant idepressant. Reboxetine pharmacokinetics is linear over a single-dose range up to 5 mg, and a multiple-dose range up to 12 mg/day. The terminal elimin ation half-life is approximately 12 h. The recommended clinical dose is 8-1 0 mg/day in two divided doses. The absolute bioavailability of reboxetine i s >94%, indicating essentially complete absorption and minimal first-pass m etabolism. Reboxetine is highly bound (>98%) to plasma proteins, primarily alpha(1)-acid glycoprotein. Less than 10% of the reboxetine dose is elimina ted in the urine as intact drug; the balance of the dose is eliminated thro ugh hepatic metabolism, predominantly via CYP3A4. Plasma concentrations of reboxetine are increased in elderly subjects and in subjects with hepatic o r renal dysfunction. The mechanism for these effects appears to be reduced metabolic clearance. Significant drug interactions do not occur between reb oxetine and quinidine or fluoxetine. Ketoconazole decreases the clearance o f reboxetine by approximately 30%. Reboxetine has no effect on the in vitro activity of CYP1A2, CYP2C9, CYP2D6, CYP2E1, or CYP3A4 at therapeutic conce ntrations. In vivo reboxetine has no effect on the dextromethorphan/dextror phan ratio, a measure of CYP2D6 activity. Thus, reboxetine is not expected to affect the pharmacokinetics of other drugs metabolized by cytochrome P45 0. Reboxetine is a racemic mixture; the S,S(+) enantiomer is apparently res ponsible for the therapeutic and adverse effects seen after reboxetine admi nistration. The ratio of area under the curve values for R,R(-) to S,S(+) r eboxetine is approximately 2:1. Chiral inversion does not occur, and pharma cokinetic differences between enantiomers are the result of stereoselective protein binding.