Dose-response evaluation of the interaction between sertraline and alprazolam in vivo.
In vitro data show the inhibition of alprazolam metabolism by sertraline via CYP3A4; therefore, using a randomized, double-blind, placebo-controlled design, the authors conducted this study to assess the potential for similar in vivo inhibition in humans. Ten healthy volunteers participated in two test sessions (placebo/alprazolam 1 mg orally) before the initiation of sertraline treatment. Blood samples were obtained over a 32-hour period and pharmacodynamic measures (sedation, psychomotor performance, memory function) were obtained over an 8-hour period. After a minimum of 2 weeks of daily sertraline self-administration (50, 100, or 150 mg/day), test sessions were repeated. Alprazolam concentrations (N = 6, 4, and 6 at sertraline doses of 50, 100, and 150 mg/day, respectively) showed no significant changes based on peak concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (t1/2[beta]), and area under the concentration-time curve (AUC(0-8)), with the exception of a reduced Cmax in the 50 mg/day group. Similarly, dynamic data showed no significant variations based on peak effect, Tmax, and AUC(0-infinity), with the exception of increased peak impairment in one measure of psychomotor performance. No differences were detected between placebo alone and placebo plus sertraline. These findings suggest that sertraline (50-150 mg/day) does not alter the single-dose kinetics or dynamics of alprazolam; therefore, the combination may be prescribed without an increased risk of alprazolam toxicity.
Hassan
P C
PC
Sunnybrook Health Science Centre, the Department of Pharmacology, University of Toronto, Ontario, Canada.
Sproule
B A
BA
Naranjo
C A
CA
Herrmann
N
N
D000328:Adult; D000525:Alprazolam / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D011939:Mental Recall / Q000187:drug effects; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D009483:Neuropsychological Tests; D011597:Psychomotor Performance / Q000187:drug effects; D020280:Sertraline / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics
D014151:Anti-Anxiety Agents; D018687:Antidepressive Agents, Second-Generation; D065607:Cytochrome P-450 Enzyme Inhibitors; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D020280:Sertraline; D000525:Alprazolam