DESIPRAMINE PHARMACOKINETICS WHEN COADMINISTERED WITH PAROXETINE OR SERTRALINE IN EXTENSIVE METABOLIZERS

In vitro studies have shown that fluoxetine and paroxetine are more po tent inhibitors of cytochrome CYP2D6 than sertraline. The pharmacokine tics of desipramine when coadministered with the selective serotonin r euptake inhibitors (SSRIs) paroxetine and sertraline were studied in 2 4 healthy male volunteers (CYP2D6 extensive metabolizers). Desipramine (50 mg/day) was administered for 23 days in each phase of the crossov er study with a 7-day drug-free period between phases. In addition, su bjects were randomly assigned to receive concomitant paroxetine (20 mg /day on days 8 through 17 followed by 30 mg/day on days 18 through 20) or sertraline (50 mg/day on days 8 through 17 and 100 mg/day on days 18 through 20), SSRI treatments were switched between phases. After 10 days of coadministration at the lower dose, mean desipramine maximum concentration in plasma (C-max) relative to baseline increased from 37 .8 to 173 ng/mL (+358%) with paroxetine versus from 36.1 to 51.9 ng/mL (+44%) with sertraline; the mean desipramine 24-hour area under the c oncentration-time curve (AUC[24]) increased from 634 to 3,305 ng.h/mL (+421%) with paroxetine versus from 611 to 838 ng.h/mL (+37%) with ser traline; and the mean desipramine trough value (C-0) increased from 18 .5 to 113 ng/mL (+511%) with paroxetine versus from 18.3 to 21.8 ng/mL (+19%) with sertraline (all increases, p < 0.001). An approximately 1 0-fold increase in the C-max and AUC(24) of paroxetine and an approxim ately 2-fold increase in these parameters for sertraline occurred simu ltaneously with the desipramine concentration changes. Thus, when coad ministered with 50 mg/day desipramine, sertraline had significantly le ss pharmacokinetic interaction than paroxetine with desipramine at the recommended starting dosages of 50 mg/day and 20 mg/day, respectively .