Pharmacokinetics of acute and sub-chronic aripiprazole in P-glycoprotein deficient mice.
BACKGROUND
P-glycoprotein (P-gp), an efflux transporter localized in the blood-brain barrier, limits the access of multiple xenobiotics to the central nervous system (CNS). For the new antipsychotic aripiprazole and its active metabolite dehydroaripiprazole differences in disposition in blood and brain were investigated after acute and sub-chronic administration in a P-gp knockout mouse model.


METHODS
Serum and brain concentrations of both drugs were measured at several time points 1-24h after i.p. injection of 10mg/kg aripiprazole and after 11 days of sub-chronic administration in several tissues. Moreover, the expression of P-gp was determined by Western blot analysis after sub-chronic administration of the drug.


RESULTS
In both wild type and abcb1ab (-/-) mice concentration of aripiprazole in brain were up to 9 fold higher than in serum. For dehydroaripiprazole the mean brain to serum ratios were below two. Brain to serum concentrations of both substances were significantly higher after acute and sub-chronic administration in connection to the expression of P-gp indicated by higher levels in abcb1ab (-/-) mice especially for dehydroaripiprazole. Sub-chronic aripiprazole treatment in WT animals had no effect on P-gp expression in the blood-brain barrier.


CONCLUSIONS
Aripiprazole and, even more pronounced its active metabolite dehydroaripiprazole could be identified as substrates of P-gp. The efflux transporter P-gp must therefore be considered as a relevant factor that contributes to wanted or unwanted clinical effects in patients treated with aripiprazole.
Kirschbaum
Katrin M
KM
Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Untere Zahlbacher Strasse 8, D-55131 Mainz, Germany.
Uhr
Manfred
M
Holthoewer
David
D
Namendorf
Christian
C
Pietrzik
Claus
C
Hiemke
Christoph
C
Schmitt
Ulrich
U
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics; D000068180:Aripiprazole; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D010879:Piperazines / Q000493:pharmacokinetics*; D015363:Quinolones / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole