Influence of blood-brain barrier efflux pumps on the distribution of vincristine in brain and brain tumors.
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.
Wang
Fan
F
James M. Gallo, Pharm.D., PhD, Department of Pharmacology and System Therapeutics Mount Sinai School of Medicine One Gustave L. Levy Pl Box 1603 New York, NY 10029, USA.
Zhou
Feng
F
Kruh
Gary D
GD
Gallo
James M
JM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000032:analysis / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism*; D002853:Chromatography, Liquid; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D014750:Vincristine / Q000032:analysis / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014750:Vincristine; C421109:multidrug resistance-associated protein 1