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The effect of P-glycoprotein on paclitaxel brain and brain tumor distribution in mice.

It may be inferred from the presence of P-glycoprotein (Pgp) in brain capillaries that this drug efflux pump is a factor in limiting the penetration of certain agents into brain tumors. However, by contrast with normal brain capillaries which constitute the blood-brain barrier, brain tumor capillaries are compromised or "leaky," and the extent to which Pgp expression in brain tumor neovasculature retains its capacity to limit drug penetration has not been determined. To address this question, we studied the normal brain and brain tumor distribution of paclitaxel (PAC), a known Pgp substrate, using steady-state PAC dosing regimens in wild-type and Pgp knockout (mdr1a -/- and mdr1b -/-) mice bearing an intracerebral B-16 melanoma. At comparable steady-state PAC plasma concentrations of approximately 5 microg/ml, steady-state PAC brain concentrations in Pgp knockout mice were approximately 3-, 1.8-, and 1.7-fold greater in left brain, right brain, and brain tumor, respectively, than in wild-type mice and statistically different (P < 0.05) in each brain region. Determination of the steady-state brain/plasma concentration ratios or partition coefficients, which take into account any differences in plasma concentrations between each group, indicated a similar pattern as did the absolute brain concentrations. It is concluded that even in the neovasculature of brain tumors, Pgp has the facility to limit drug penetration, although somewhat less so than in normal brain.