Dl. Kurtz et al., THE EFFECT OF SERTRALINE ON THE PHARMACOKINETICS OF DESIPRAMINE AND IMIPRAMINE, Clinical pharmacology and therapeutics, 62(2), 1997, pp. 145-156
Objective: To examine the pharmacokinetic interaction between the sele
ctive serotonin reuptake inhibitor sertraline and the tricyclic antide
pressants desipramine or imipramine in 12 healthy male subjects. Metho
ds: Participants received a 50 mg single dose of either desipramine or
imipramine under three conditions: alone, after a single 150 mg dose
of sertraline, and after the eighth daily 150 mg dose of sertraline. P
lasma samples were analyzed for desipramine or imipramine concentratio
n by HPLC with electrochemical detection, and pharmacokinetics were de
termined with use of noncompartmental analysis of individual data. Res
ults: Multiple-dose, but not single-dose, treatment with sertraline si
gnificantly reduced apparent plasma clearance (CL/F) and prolonged the
half-life of desipramine relative to baseline. These changes resulted
in higher plasma desipramine concentrations, as indicated by a signif
icant increase in maximum plasma concentration (C-max) and area under
the plasma concentration-time curve extrapolated to infinity [AUC(0-in
finity)] (22% and 54%, respectively). Both single-and multiple-dose tr
eatment with sertraline significantly reduced the CL/F of imipramine.
This effect was stronger after multiple predoses of sertraline, when i
mipramine C-max and AUC(0-infinity) were increased by 39% and 68%, res
pectively. These treatment effects were consistent between individuals
. Conclusions: This pharmacokinetic interaction is likely the result o
f an inhibition of CYP2D6 tricyclic metabolism by sertraline. When a t
ricyclic antidepressant, such as desipramine or imipramine, is coadmin
istered with sertraline, lower dosages of the tricyclic agents may be
necessary to prevent elevated tricyclic levels.