Aripiprazole brain concentration is altered in P-glycoprotein deficient mice.

P-glycoprotein (P-gp) is a transporter that mediates the tissue disposition of numerous drugs. To evaluate the role of P-glycoprotein (P-gp) in aripiprazole tissue distribution and penetration across the blood-brain barrier, mice deficient in the P-gp gene (Abcb1a/b-/-) were dosed intraperitoneally with 2 microg/g mouse of the antipsychotic drug aripiprazole. Wildtype FVB mice were administered the same dose as transgenic animals. At one, two, and three hours after dosing, blood and tissue samples were collected and assayed for aripiprazole concentration by HPLC. Deficiency of P-gp did not result in significantly altered plasma drug concentrations but had dramatic effects on drug concentrations in brain tissue. At 1, 2, and 3 h after dosing, aripiprazole brain concentrations in the Abcb1a/b-/- mice were 4.6-, 4.1- and 3.0-fold higher, respectively (P<0.01), compared with the wildtype mice. Increases in drug concentration were also observed in testes and muscle in Abcb1a/b -/- mice. All other tissues including gut, lung, heart, kidney, liver, and spleen did not show significant differences between the two groups. These data provide evidence that aripiprazole is a transportable substrate of P-gp. Thus, factors influencing P-gp activity within the blood brain barrier in humans may have implications for the therapeutic effects and tolerability of aripiprazole.