Pharmacokinetics of acute and sub-chronic aripiprazole in P-glycoprotein deficient mice

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.

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.

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.

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.