Inhibition of P-glycoprotein function by several antidepressants may not contribute to clinical efficacy.
BACKGROUND
In many depressive patients the negative feedback mechanism of the HPA (hypothalamic-pituitary-adrenocortical) axis is impaired. It has been suggested that antidepressants inhibit membrane glucocorticoid transporters like P-Glycoprotein (Pgp) and hence enhance the intracellular glucocorticoid concentration, leading to an increased glucocorticoid-receptor mediated gene transcription and therefore to normalization of the function of the HPA axis. The aim of this study is to investigate inhibition of Pgp by several different antidepressants.


METHODS
We characterized the inhibitory potencies of the antidepressants in two in vitro assays by using calcein-AM as Pgp substrate. The two different cell-systems expressing Pgp were: 1. PBCEC (porcine brain capillary endothelial cells) as model for the blood-brain-barrier, and 2. A human lymphocytic leukaemia cell line CEM and the multi-drug-resistant (MDR) cell line VLB-100, expressing Pgp as model for the human protein.


RESULTS
All of the antidepressants tested inhibit the transport of calcein-AM by Pgp in the micromolecular range.


CONCLUSIONS
Because this inhibition is only seen at concentrations above therapeutically relevant plasma levels, their effect my not play a role for the mechanism of action of the antidepressants tested.
Weber
C C
CC
Department of Pharmacology, Biocenter, University of Frankfurt, Frankfurt, Germany.
Kressmann
S
S
Ott
M
M
Fricker
G
G
Müller
W E
WE
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects; D002196:Capillaries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013552:Swine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000255:Adenosine Triphosphate; D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006861:Hydrogen Peroxide; D016877:Oxidants; D017367:Selective Serotonin Reuptake Inhibitors; C085925:calcein AM