THE EFFECTS OF DESIPRAMINE AND IPRINDOLE ON LEVELS OF ENANTIOMERS OF FLUOXETINE IN RAT-BRAIN AND URINE

The antidepressant fluoxetine (FLU) and its N-demethylated metabolite, norfluoxetine (NFLU), each contains a chiral center. The combination of FLU and desipramine (DMI), another antidepressant, has been reporte d to be useful in treatment of depression, to dramatically increase pl asma levels of DMI and also to produce more rapid P-adrenergic recepto r down-regulation in brain than caused by DMI alone. We have now begun studies on the effects of this drug combination on the levels of FLU and NFLU enantiomers in the rat. In addition, the combination of FLU a nd iprindole (IPR) was also investigated. Male Sprague-Dawley rats wer e treated intraperitoneally with either normal saline vehicle, DMI (5 mg/kg/day), (R,S)-FLU (10 mg/kg/day) or DMI (5 mg/kg/day ) + (R,S)-FLU (10 mg/kg/day) for 4 days. Following the last treatment, 24 h urine s amples were collected. Rats were sacrificed and brains were removed. F or the IPR study, rats were pretreated with either saline or IPR-HCl ( 11.2 mg/kg) and then treated 1 h later with (R,S)-FLU. After 5 h, the rats were sacrificed and brains were removed. Brain and urine samples were analyzed by gas chromatography with electron-capture detection fo r free (R)and (S)-FLU and (R)- and (S)-NFLU after extraction and react ion with (-)-(S)-N-(trifluoro-acetyl)prolyl chloride. The results from the brains of the rats treated with DMI/FLU indicate that levels of t he enantiomers of both FLU and NFLU were significantly increased over those seen in the animals receiving (R, S)-FLU alone. In the IPR/FLU t reated rats, an increase in the brain levels of both (R)- and (S)-FLU was noted when compared with rats receiving (R,S)-FLU alone; however, there appeared to be no increase in the brain levels of NFLU enantiome rs. (C) 1994 Wiley-Liss, Inc.