CYP2D6 Status of Extensive Metabolizers After Multiple-Dose Fluoxetine, Fluvoxamine, Paroxetine, or Sertraline

Abstract

The aim of this study was to evaluate the CYP2D6 inhibitory effects of four selective rerotonin re-uptake inhibitors (SSRIs). Thirty-one healthy subjects were phenotyped as extensive metabolizers using the dextromethorphan/dextrorphan (DM/DX) urinary ratio as a marker for CYP2D6 activity before and after 8 days of administration of fluoxetine 60 mg (loading dose strategy), fluvoxamine 100 mg, paroxetine 20 mg, or sertraline 100 mg in a parallel-group design. Statistical analysis was performed on log-transformed DM/DX ratios because of variability within and between treatment groups. DM/DX ratios before (DM/DX(BL)) and after (DM/DX(SSRI)) were compared within and between the four SSRI groups. DM/DX(BL) ratios were not significantly different between the four SSRI treatment groups. Comparing within groups, significant differences between DM/DX(BL) and DM/DX(SSRI) were found for the fluoxetine (p < 0.001; ratio values, 0.020 vs. 0.364) and paroxetine (p = 0.0005, ratio values 0.029 vs. 1.085) but not for the fluvoxamine or sertraline groups. Comparing between groups, significant differences in DM/DX(SSRI) ratios were found for fluoxetine versus sertraline (p = 0.0019, DM/DX = 0.364 vs. 0.057), fluoxetine versus fluvoxamine (p < 0.0001, DM/DX = 0.364 vs. 0.019), paroxetine versus sertraline (p = 0.0026, DM/DX = 1.085 vs. 0.057), and paroxetine versus fluvoxamine (p < 0.0001, DM/DX = 1.085 vs. 0.019). No significant differences were noted between the two potent CYP2D6 inhibitors, fluoxetine and paroxetine, or the two weakest inhibitors, fluvoxamine and sertraline. Five subjects in the fluoxetine and four subjects in the paroxetine groups changed to poor metabolizer phenotype (DM/DX > or = 0.3) after treatment. Although CYP2D6 inhibitory effects of fluvoxamine and sertraline did not yield significant differences from baseline, some subjects exhibited DM/DX ratio increases of 150 to 200%. One paroxetine-treated subject did not exhibit any CYP2D6 inhibition. SSRI dose and plasma concentration may be correlated with the extent of CYP2D6 inhibition and should be further investigated.

Effect of fluvoxamine on plasma risperidone concentrations in patients with schizophrenia

“…In this respect, in vitro research has demonstrated that fluvoxamine has a weaker inhibitory effect on CYP2D6 activity as compared to other SSRIs such as fluoxetine, norfluoxetine and paroxetine [15,17,19]. Consistent with this, fluvoxamine, 100 mg/day, has been reported to have relatively modest in vivo effects on CYP2D6 substrates such as dextromethorphan [30] and desipramine [31]. To explain the minimal elevation in total plasma risperidone levels and the associated increase in risperidone/9-OH-risperidone ratio in the subgroup of subjects receiving the highest fluvoxamine dose, it can be speculated a dose-dependent inhibitory effect of fluvoxamine on the 9-hydroxylation of risperidone, presumably mediated by inhibition of CYP2D6 and/or CYP3A4.…”

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

“…Therefore, multiple dosing causes decreased CYP2D6-mediated metabolism of the drugs themselves, and conversion from extensive to slow metabolizer phenotype and from ultrarapid to extensive metabolism was described. [124][125][126][127] Unfortunately, these studies for fluoxetine and fluvoxamine describing conversion from higher to lower enzyme activity have studied the effect of enzyme inhibition only in one genotype group 40,127 and could therefore not be used in our dose calculation approach.…”

Apparent Mechanism-based Inhibition of Human CYP2D6 in Vitro by Paroxetine: Comparison with Fluoxetine and Quinidine

“…Nonetheless usual doses and plasma levels of paroxetine can produce extensive inhibition of clearance of coadministered drugs that are substrates for CYP2D6 (Brøsen et al, 1993;Alderman et al, 1997;Ö zdemir et al, 1998;Alfaro et al, 1999). Approaches to predicting clinical pharmacokinetic drug interactions based on in vitro data continue to be controversial (Bertz and Granneman, 1997;Ito et al, 1998;von Moltke et al, 1998b;Venkatakrishnan et al, 2001).…”