Differential enhancement of antidepressant penetration into the brain in mice with abcb1ab (mdr1ab) P-glycoprotein gene disruption.
BACKGROUND
Mice with a genetic disruption (knockout) of the multiple drug resistance (abcb1ab) gene were used to examine the effect of the absence of the drug-transporting P-glycoprotein (P-gp) at the blood-brain barrier on the uptake of the antidepressants venlafaxine, paroxetine, mirtazapine, and doxepin and its metabolites into the brain.


METHODS
One hour after subcutaneous injection of venlafaxine, paroxetine, mirtazapine, or doxepin, knockout and wildtype mice were sacrificed, and the drug concentrations in brain, spleen, kidney, liver, and plasma were measured.


RESULTS
The cerebrum concentrations of doxepin, venlafaxine, and paroxetine were higher in knockout mice, demonstrating that these substances are substrates of P-gp and that abcb1ab activity at the level of the blood-brain barrier reduces the penetration of these substances into the brain. In contrast, brain distribution of mirtazapine was indistinguishable between the groups.


CONCLUSIONS
The differences reported here in brain penetration of antidepressant drugs that depend on the presence of the abcb1ab gene may offer an explanation for poor or nonresponse to antidepressant treatment. Furthermore, they may be able to explain in part the discrepancies between plasma levels of an antidepressant and its clinical effects and side effects.
Uhr
Manfred
M
Max Planck Institute of Psychiatry, Kraepelinstrasse 10, D-80804 Munich, Germany.
Grauer
Markus T
MT
Holsboer
Florian
F
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003511:Cyclohexanols / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004316:Doxepin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics; D007279:Injections, Subcutaneous; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008803:Mianserin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D051379:Mice; D018345:Mice, Knockout; D000078785:Mirtazapine; D017374:Paroxetine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D017354:Point Mutation / Q000235:genetics*; D013154:Spleen / Q000378:metabolism; D000069470:Venlafaxine Hydrochloride; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000928:Antidepressive Agents; D003511:Cyclohexanols; D004316:Doxepin; D008803:Mianserin; D000078785:Mirtazapine; D017374:Paroxetine; D000069470:Venlafaxine Hydrochloride; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3