Review of the pharmacokinetics and metabolism of reboxetine, a selective noradrenaline reuptake inhibitor.
The pharmacokinetics and metabolism of reboxetine, a selective noradrenaline reuptake inhibitor, in humans and animal models are reviewed here. Reboxetine has potent antidepressant activity, low affinity for alpha-adrenergic and muscarinic receptors and low toxicity in animals. It is a mixture of (R,R) and (S,S) enantiomer, the latter being more potent but no qualitative differences in pharmacodynamic properties are observed between the two. Humans rapidly absorb reboxetine (tmax about 2 h) with a terminal half-life of elimination (t1/2) of 13 h, allowing twice-daily administration. Animal models also rapidly absorb reboxetine (tmax 0.5-2 h) but t1/2 was 1-2 h. Food does not affect bioavailability. There were no major inter-species differences in the metabolic profile of reboxetine. Elimination is principally renal in humans and monkeys. Reboxetine has linear pharmacokinetics in young, healthy males for single doses of 1-5 mg and in elderly, female depressed patients (up to 4 mg b.i.d.). Multiple dosing, gender or liver insufficiency had no significant effects on the pharmacokinetics. Elderly (particularly frail elderly) patients and patients with severe renal impairment may need dose reduction. Reboxetine shows no clinically relevant interaction with lorazepam and has no inhibitory effects on the major enzymes involved in drug metabolism. It may be possible to use reboxetine in combination with monoamine oxidase inhibitors as it has no inhibitory effect on this enzyme; in addition, it may protect patients against tyramine-induced reactions. In conclusion, reboxetine seems to be an antidepressant with negligible interference with the pharmacokinetics of other drugs thus fewer drug-drug interactions are expected.
Dostert
P
P
Pharmacia and Upjohn, Pharmacokinetics and Metabolism Department, Milan, Italy.
Benedetti
M S
MS
Poggesi
I
I
D018759:Adrenergic Uptake Inhibitors / Q000493:pharmacokinetics*; D000367:Age Factors; D000818:Animals; D000928:Antidepressive Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D018565:Food-Drug Interactions; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008107:Liver Diseases / Q000378:metabolism; D009025:Morpholines / Q000493:pharmacokinetics* / Q000652:urine; D000077593:Reboxetine; D013237:Stereoisomerism
D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D009025:Morpholines; D000077593:Reboxetine