Influence of blood-brain barrier efflux pumps on the distribution of vincristine in brain and brain tumors

Abstract

Vincristine (VCR) is efficacious in some but not all brain cancers and an established substrate of Pgp and Mrp1. However, the extent to which such transporters affect the VCR penetration through the blood-brain barrier (BBB) is poorly understood. To evaluate the role of Pgp and Mrp1 in VCR CNS distribution, VCR concentrations were analyzed under steady-state conditions in normal brain, brain tumor, and bone marrow in wild-type (WT), Mrp1 ko (mrp1-/-), Pgp ko (mdr1a-/-:mdr1b-/-), and TKO (mdr1a-/-:mdr1b-/-:mrp1-/-) mice. VCR normal brain partition coefficients (i.e. tissue/plasma VCR concentrations) in TKO mice were greater than those in WT mice at both targeted 10 and 50 ng/mL plasma VCR concentrations, and ranged from 1.3- to 3.6-fold. VCR brain tumor partition coefficients in Mrp1 mice were greater than WT mice at both doses, being 1.5- and 2.4-fold higher at low and high doses, respectively. TKO mice also showed elevated VCR brain tumor penetration with a brain tumor partition coefficient of 1.9-fold greater than that in WT mice at the high-dose level. The bone marrow partition coefficient in Mrp1 ko mice was 1.65-fold greater than that in WT mice. Within strain comparisons revealed that VCR brain tumor concentrations were significantly greater than normal brain in all strains, ranging from 9- to 40-fold. These findings indicate that disruption of the BBB caused the largest enhancement in VCR tumor concentrations, yet the absence of Mrp1 on the brain tumor vasculature could enhance the penetration compared with that in normal brain.

Fig. 1.

Mean (±SD) VCR plasma concentrations at 60, 120, 180, and 240 minutes. VCR was administered as a combined IV bolus dose and a 4 hour IV infusion designed to achieve plasma concentrations of 10 ng/mL (low dose, n = 6, filled symbols) and 50 ng/mL (high dose, n = 10, open symbols), respectively. Between 180 and 240 minutes, VCR plasma concentration reached steady state in both low- and high-dose study. WT (circle); Mrp1 ko (square); Pgp ko (triangle); TKO (inverted triangle).

Fig. 2.

Steady-state VCR concentration ratios in tissues of wild-type and knock out mouse strains. (A) Low-dose study targeting ∼10 ng/mL; (B) high-dose study targeting ∼50 ng/mL. For the low-dose group, concentration ratios are shown for left brain, right brain, and brain tumor; for the high-dose group, concentration ratios are shown for left brain, right brain, brain tumor, and bone marrow. WT (open bar); Mrp 1 ko (horizontal stripes); Pgp ko (vertical stripes); TKO (dots). Mean (±SD) are shown; the data are from Table 1. *P < 0.05; **P < 0.01; ***P < 0.001 compared with WT using student's t-test.