FLUVOXAMINE AND FLUOXETINE - INTERACTION STUDIES WITH AMITRIPTYLINE, CLOMIPRAMINE AND NEUROLEPTICS IN PHENOTYPED PATIENTS

The in vivo pharmacokinetic interaction between two selective serotoni n reuptake inhibitors (SSRI) (fluvoxamine, fluoxetine) and tricyclic a ntidepressants (TCAs) (amitriptyline, clomipramine) or neuroleptics (h aloperidol, cyamemazine, levomepromazine, propericiazine) was assessed in 29 in-patients. They were phenotyped twice with dextromethorphan a nd mephenytoin: first in steady state conditions while under treatment with TCAs or neuroleptics; and also 10 days after an associated treat ment with fluvoxamine (150 mg day(-1)) or fluoxetine (20 mg day(-1)). A clear and statistically significant increase in the mean urinary met abolic ratio (MR) of dextromethorphan/dextrorphan and in the mean meph enytoin S/R ratio (S/R) was seen with the fluvoxamine and fluoxetine t reatment. The mean MR increased from 0.13 to 0.27 (P<0.01) with fluoxe tine and from 0.34 to 0.84 with fluvoxamine (P<0.05). The (dextrometho rphan) 'extensive metabolizer' phenotype switched to the 'poor metabol izer' phenotype in six patients by the 10-day fluoxetine treatment, an d in two patients by the fluvoxamine treatment. The mean S/R increased from 0.24 to 0.34 (P<0.05) with fluoxetine, and from 0.33 to 0.58 (P< 0.002) with fluvoxamine. These results are in agreement with the obser ved modification of TCA plasma levels after the SSRI association. Duri ng fluvoxamine treatment, amitriptyline and clomipramine plasma levels (P<0.06 both) tendentially increased, and those of demethylclomiprami ne decreased (P<0.06). Fluoxetine addition lead to a significant incre ase (P<0.02) of the desmethyl-clomipramine plasma levels. Fluvoxamine induced a moderate augmentation of the plasma levels of haloperidol an d its reduced metabolite and no change in the plasma levels of cyamema zine and levomepromazine. But patients treated with neuroleptics are t o few to draw any firm conclusion. This study suggests, that fluoxetin e and fluvoxamine differ in their interaction with the metabolism of s ome other basic psychotropic drugs, by a mechanism which implies CYP2D 6 and CYPmeph and possibly other isoformes of cytochrome P-450. Moreov er, the interactions produced varied with the TCA prescribed.