Reboxetine and cytochrome P450--comparison with paroxetine treatment in humans.
OBJECTIVE
The noradrenaline-selective antidepressant reboxetine in vitro is a weak inhibitor of both cytochrome P450 (CYP) 2D6 and CYP3A4. Thus, in this study the pharmacokinetics of reboxetine in relation to pharmacogenetics and the effects of reboxetine compared to paroxetine treatment on the CYP2D6 and CYP3A4 phenotype were analyzed in healthy control subjects.


METHODS
Healthy male volunteers were treated with either 6 mg reboxetine (n = 26) or 30 mg paroxetine (n = 25). On Days 10/11 of treatment, serum concentrations of the antidepressants were measured and pharmacokinetic parameters calculated. Volunteers were phenotyped at the end of treatment and after at least 3 weeks washout (true phenotype) using 30 mg dextromethorphan (DM) hydrobromide given orally and measuring DM and metabolites in serum 2 h after intake. CYP2D6 and CYP2C19 genotypes were determined in parallel.


CONCLUSIONS
Reboxetine serum concentrations showed no correlation with the CYP2D6 genotype and the CYP2D6 phenotype, whereas paroxetine concentrations showed some dependence on CYP2D6. In contrast to in vitro investigations, indicating a major role of CYP3A4 in reboxetine metabolism, reboxetine concentrations in serum showed no correlation with the respective DM metabolic ratios. There was also no correlation between paroxetine concentrations and the CYP3A4 phenotype data. The CYP2C19 genotype (only heterozygosity) had no influence on reboxetine and paroxetine pharmacokinetics. There were only minor changes in the DM metabolite pattern on treatment with reboxetine and no evidence of enzyme inhibition was obtained. In contrast and as expected, paroxetine strongly inhibited CYP2D6. Thus, reboxetine treatment has no effect on the CYP2D6 genotype and no clinically relevant drug interactions involving CYP2D6 are anticipated.
Kuhn
U D
UD
Institute of Clinical Pharmacology, Friedrich Schiller University, Jena, Germany. urs.kuhn@med.uni-jena.de
Kirsch
M
M
Merkel
U
U
Eberhardt
A M
AM
Wenda
B
B
Maurer
I
I
Härtter
S
S
Hiemke
C
C
Volz
H P
HP
Balogh
A
A
D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000328:Adult; D000928:Antidepressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D003915:Dextromethorphan / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D005838:Genotype; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009025:Morpholines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D009154:Mutation; D017374:Paroxetine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D010641:Phenotype; D000077593:Reboxetine; D012016:Reference Values; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D003915:Dextromethorphan; D004791:Enzyme Inhibitors; D006899:Mixed Function Oxygenases; D009025:Morpholines; D017374:Paroxetine; D000077593:Reboxetine; D017367:Selective Serotonin Reuptake Inhibitors; C045793:CYP2C19 protein, human; C510163:CYP3A4 protein, human