Kinetic Interaction between Fluoxetine and Imipramine as a Function of Elevated Serum Alpha-1-acid Glycoprotein Levels

Abstract

The effect of elevated serum alpha-1-acid glycoprotein (AAG) levels on the pharmacokinetic interaction between imipramine and fluoxetine has been examined by utilizing a novel strain of transgenic mice which express serum AAG levels several times greater than normal. Before fluoxetine treatment, serum imipramine levels were approximately three times greater in transgenic mice than in control mice. Despite higher serum imipramine levels in transgenic mice, brain drug levels were lower than those found in control mice. Fluoxetine pre-treatment (20 mg kg(-1) for 5 days) resulted in an increase in serum imipramine levels in both groups of mice and the extent of the increase was greater in transgenic mice than in control mice (4.5-fold increase compared with 3.1-fold). Similarly, fluoxetine pre-treatment resulted in an increase in brain levels of imipramine in both groups of mice and the extent of the increase was greater in transgenic mice than in control mice (3.0-fold increase compared with 2.0-fold). Similar trends were observed for levels of desipramine in the serum and brain. Serum imipramine and desipramine levels did not correlate with their respective brain levels in the presence of elevated serum AAG levels before and after pre-treatment. These findings indicate that the extent of increases in imipramine and desipramine serum and brain levels are greater during elevated serum AAG states than during normal AAG states when imipramine is co-administered with fluoxetine.

Clinically Relevant Doses of Fluoxetine and Reboxetine Induce Changes in the TrkB Content of Central Excitatory Synapses

“…It is also of interest that in depressed patients there is a significant increase in the plasma protein alpha 1-acid glycoprotein (AAG) (Nemeroff et al, 1990), one of the major binding sites for Flx in plasma (the other one is serum albumin). Such an increase in AAG leads to a rise in total Flx concentration in plasma, but decreases the unbound fraction leading to a decrease in Flx and NFlx concentrations in the brain (Holladay et al, 1998).…”

Fluoxetine Metabolism and Pharmacological Interactions: The Role of Cytochrome P450

“…With regard to FLU as an inhibitor of CYP, kinetic studies have demonstrated that plasma and brain levels and pharmacological efficacy of both FLU and TCAs can be increased by their simultaneous administration [66][67][68]. This interaction can be explained by the fact that FLU is both a strong inhibitor of CYP2D6 [69] and a substrate of this isozyme.…”