Pharmacokinetic pharmacodynamic evaluation of the combined administration of alprazolam and fluoxetine

Abstract

The pharmacokinetic and pharmacodynamic effects of concomitant administration of alprazolam and fluoxetine were studied in this double-blind parallel study in 80 healthy, male volunteers. Subjects were randomly assigned to one of four treatment groups. Drug treatments consisted of 4-day regimens of 1 mg alprazolam four times daily, 60 mg fluoxetine every morning, 1 mg alprazolam four times daily and 60 mg fluoxetine every morning, and placebo four times daily. Psychomotor performance, mood status, and degree of sedation were evaluated at designated times. Combined administration of alprazolam and fluoxetine resulted in an approximate 30% increase in plasma alprazolam concentrations relative to plasma concentrations following the administration of alprazolam alone. There were no significant differences in fluoxetine or norfluoxetine plasma concentrations between the alprazolam/fluoxetine and fluoxetine treatments. Psychomotor decrements increased when fluoxetine was administered with alprazolam relative to alprazolam administration alone. Psychomotor performance of the fluoxetine treatment group was not significantly different from that of the placebo group. No significant changes were observed in mood status, and sedation was minimal in all treatment groups. As when any two psychoactive drugs are administered together, increased patient monitoring and patient education is recommended when alprazolam and fluoxetine are prescribed concurrently.

Phenacetin O -deethylation by human liver microsomes in vitro: inhibition by chemical probes, SSRI antidepressants, nefazodone and venlafaxine

“…Numerous pharmacokinetic drug interactions with SSRI antidepressants have been reported in controlled studies (Lemberger et al 1988;Lasher et al 1991;Bergstrom et al 1992;Greenblatt et al 1992;Brøsen et al 1993a;Spina et al 1993;Daniel et al 1994;Fleishaker and Hulst 1994;Perucca et al 1994;Preskorn et al 1994;El-Yazigi et al 1995). However, the available SSRIs are not equally active inhibitors of any specific cytochrome, nor are the various human cytochromes equally susceptible to inhibition by any specific SSRI.…”

Sleep Laboratory Study on Single and Repeated Dose Effects of Paroxetine, Alprazolam and Their Combination in Healthy Young Volunteers

“…A lack of in vivo steady-state pharmacokinetic interaction between paroxetine and alprazolam has been observed [21] , confi rming that paroxetine does not affect either CYP3A4-mediated alprazolam hydroxylation pathway or its overall pharmacokinetic profi le. Conversely, there is evidence to suggest that other SSRIs, such as fl uoxetine [43,44] or fl uvoxamine [45] , are signifi cant in vivo inhibitors of alprazolam metabolism, thus potentially increasing the risk of alprazolam to induce central nervous system effects. A purely dynamic interaction hence seems to be the most conceivable explanation for the results obtained.…”

Alprazolam Metabolism in vitro: Studies of Human, Monkey, Mouse, and Rat Liver Microsomes

“…This is consistent with observations of linear (doseindependent) kinetics of ALP in humans [8,21,22], Available data strongly suggest that ALP oxidation is mediated by the cytochrome P-450-3A subfamily [6]. In humans, coadminis tration of ALP with other drugs that can impair activity of this enzyme system (such as cimetidine, fluoxetine, and fluvoxamine) can therefore be expected to impair ALP clear ance and elevate its plasma levels, and possi bly to increase clinical effects [22][23][24][25][26], 4-OH-ALP formation rates also exceeded those of a-OH-ALP in the three animal spe cies studied, although the extent of 4-OH-ALP predominance was much greater in rats than in monkeys or mice. All three species had higher absolute rates of a-OH-ALP for mation than those found in the human do nors.…”