Evaluation of the Potential Pharmacokinetic/Pharmacodynamic Interaction between Fluoxetine and Reboxetine in Healthy Volunteers

Fleishaker, Joseph C.; Herman, Beth D.; Pearson, Laura; Ionita, Antoaneta; Mucci, Massimiliano

doi:10.2165/00044011-199918020-00007

Cited by 16 publications

(7 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Fluoxetine had no effect on the pharmacokinetics or pharmacodynamics of reboxetine (39). As expected, quinidine, a potent inhibitor of CYP2D6, had no effect on reboxetine clearance (108).…”

Section: Factors Affecting Pharmacokineticsmentioning

confidence: 70%

See 1 more Smart Citation

The Selective Norepinephrine Reuptake Inhibitor Antidepressant Reboxetine: Pharmacological and Clinical Profile

et al. 2004

Self Cite

View full text Add to dashboard Cite

Reboxetine is the first commercially available norepinephrine reuptake inhibitor developed specifically as a first line therapy for major depressive disorder. In vitro and in vivo pharmacological studies indicated that reboxetine methanesulphonate has high affinity and selectivity for the human norepinephrine transporter over the serotonin and dopamine transporters. Pharmacological specificity is further demonstrated by the absence of affinity for 45 transmitter receptors and CNS targets. Pharmacokinetic studies demonstrated that reboxetine is suitable for twice daily administration (8-10 mg/day) and that it exhibits minimal drug-drug interactions. The starting dose of reboxetine should be reduced in the elderly, in patients with renal or hepatic impairment, or in patients receiving potent CYP3A inhibitors. A total of 20 phase II/III clinical studies comprising placebo-controlled, active comparator-controlled and open-label uncontrolled studies in both short-term and long-term treatment of major depression have been conducted. In the treatment of major depression, reboxetine was superior to placebo in 5 of 12 short- or long-term placebo-controlled studies and was comparable in efficacy to active comparators in 3 out of 3 active-controlled studies. Unlike conventional tricyclic antidepressants (TCAs), reboxetine had only minimal sedative and cardiovascular liabilities, probably due to increased pharmacological specificity of reboxetine as compared with TCAs. Unlike serotonin reuptake inhibitors, this selective and specific norepinephrine reuptake inhibitor demonstrated a distinct side-effect profile with diminishing sexual dysfunction and GI side effects. The availability of this agent has afforded patients suffering from major depressive disorder a new class of agents to combat the debilitating consequence of this psychiatric disease. The demonstrated pharmacological specificity of this compound has provided the psychopharmacology community with a tool to elucidate the role of norepinephrine in brain functions. Testing this agent in different animal models has enabled the exploration of the role of modulation of norepinephrine tone in the therapy of CNS disorders beyond depression.

show abstract

“…Fluoxetine had no effect on the pharmacokinetics or pharmacodynamics of reboxetine (39). As expected, quinidine, a potent inhibitor of CYP2D6, had no effect on reboxetine clearance (108).…”

Section: Factors Affecting Pharmacokineticsmentioning

confidence: 70%

“…Following multiple dose administration the pharmacokinetics of reboxetine is linear through a dose of 12 mg/day (39). Plasma levels at a steady-state are approximately twice those following single dose administration, indicating a modest degree of accumulation (96).…”

Section: Pharmacokineticsmentioning

confidence: 99%

The Selective Norepinephrine Reuptake Inhibitor Antidepressant Reboxetine: Pharmacological and Clinical Profile

et al. 2004

Self Cite

View full text Add to dashboard Cite

show abstract

“…RBX doses of 30, 20, 10, 5, and 2.5 mg/kg/day produced serum values of 1196 7 122, 191 7 38, 86 7 18, 40 7 7, and 20 7 2 ng/ml, respectively. The RBX concentration used in this study was 20 mg/kg/day, which produced a serum concentration close to human therapeutic values (Fleishaker et al, 1999). As the affinity of RBX for the rat and human NET is comparable (Wong et al, 2000), attaining 'therapeutic' serum concentrations is relevant for a study in rats.…”

Section: Animals and Chronic Drug Treatmentsmentioning

confidence: 87%

Regulatory Effects of Reboxetine Treatment Alone, or Following Paroxetine Treatment, on Brain Noradrenergic and Serotonergic Systems

Gould

Pardon

Morilak

et al. 2003

Neuropsychopharmacol

View full text Add to dashboard Cite

When patients do not respond to an initial antidepressant, one clinical approach is to switch to an agent in a different pharmacological class. However, few studies have examined the neurochemical consequences of this practice. To study this, we examined changes in binding sites in rat brain for norepinephrine (NET) and serotonin transporters (SERT), a 1 , a 2 , and b 1 adrenergic receptors after chronic administration of paroxetine (PRX), reboxetine (RBX), or PRX followed by RBX. We also examined the effects of these treatments on mRNA expression for tyrosine hydroxylase (TH). RBX treatment for 3 weeks reduced NET binding significantly, by B40% in terminal field areas, and 6 weeks of RBX reduced it even more, by B60%. RBX treatment for 3 and 6 weeks reduced b 1 adrenergic receptorbinding sites equally, by 50-60%. At no time did RBX treatment reduce SERT-binding sites. PRX treatment had no effect on b 1 adrenergic or NET-binding sites, but reduced SERT-binding sites by 75-80%. Neither treatment altered mRNA for TH, a 1 , or a 2 adrenergic receptor-binding sites. When 3 weeks of RBX treatment followed 3 weeks of PRX treatment, NET-binding sites were reduced to the same extent as measured after 6 weeks of RBX treatment alone, indicating that PRX pretreatment may have 'primed' the subsequent regulatory effect of RBX on the NET. Thus, pretreatment of rats with PRX actually enhanced at least one regulatory effect of RBX treatment on the noradrenergic system, and did not interfere with any other pharmacological effect caused by RBX treatment.

show abstract

“…Studies in healthy volunteers have indicated that reboxetine does not affect pharmacokinetic parameters of lorazepam and fluoxetine [147,148]. In a recent study of patients with schizophrenia or schizoaffective disorder with associated depressive symptoms, coadministration of reboxetine, 8 mg/day, for 4 weeks did not affect plasma concentrations of clozapine (seven patients), risperidone (seven patients) and their active metabolites [149].…”

Section: Reboxetinementioning

confidence: 99%

Metabolic drug interactions with new psychotropic agents

Spina

Scordo

D'Arrigo

2003

Fundamemntal Clinical Pharma

118

104

View full text Add to dashboard Cite

New psychotropic drugs introduced in clinical practice in recent years include new antidepressants, such as selective serotonin reuptake inhibitors (SSRI) and 'third generation' antidepressants, and atypical antipsychotics, i.e. clozapine, risperidone, olanzapine, quetiapine, ziprasidone and amisulpride. These agents are extensively metabolized in the liver by cytochrome P450 (CYP) enzymes and are therefore susceptible to metabolically based drug interactions with other psychotropic medications or with compounds used for the treatment of concomitant somatic illnesses. New antidepressants differ in their potential for metabolic drug interactions. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, fluvoxamine markedly inhibits CYP1A2 and CYP2C19, while nefazodone is a potent inhibitor of CYP3A4. These antidepressants may be involved in clinically significant interactions when coadministered with substrates of these isoforms, especially those with a narrow therapeutic index. Other new antidepressants including sertraline, citalopram, venlafaxine, mirtazapine and reboxetine are weak in vitro inhibitors of the different CYP isoforms and appear to have less propensity for important metabolic interactions. The new atypical antipsychotics do not affect significantly the activity of CYP isoenzymes and are not expected to impair the elimination of other medications. Conversely, coadministration of inhibitors or inducers of the CYP isoenzymes involved in metabolism of the various antipsychotic compounds may alter their plasma concentrations, possibly leading to clinically significant effects. The potential for metabolically based drug interactions of any new psychotropic agent may be anticipated on the basis of knowledge about the CYP enzymes responsible for its metabolism and about its effect on the activity of these enzymes. This information is essential for rational prescribing and may guide selection of an appropriate compound which is less likely to interact with already taken medication(s).

show abstract

Evaluation of the Potential Pharmacokinetic/Pharmacodynamic Interaction between Fluoxetine and Reboxetine in Healthy Volunteers

Cited by 16 publications

References 14 publications

The Selective Norepinephrine Reuptake Inhibitor Antidepressant Reboxetine: Pharmacological and Clinical Profile

The Selective Norepinephrine Reuptake Inhibitor Antidepressant Reboxetine: Pharmacological and Clinical Profile

Regulatory Effects of Reboxetine Treatment Alone, or Following Paroxetine Treatment, on Brain Noradrenergic and Serotonergic Systems

Metabolic drug interactions with new psychotropic agents

Contact Info

Product

Resources

About