bcrp - publications

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1. Mol Pharm. 2012 Feb 15. [Epub ahead of print]

Insight into the Cooperation of P-glycoprotein (ABCB1) and Breast Cancer
Resistance Protein (ABCG2) at the Blood-Brain Barrier: A Case Study Examining
Sorafenib Efflux Clearance.

Agarwal S, Elmquist WF.

The ATP-binding cassette transporters p-glycoprotein and breast cancer resistance
protein have been shown to be critical determinants limiting drug transport
across the BBB into the brain. Several therapeutic agents have been shown to be
substrates for these two transporters, and as a result they have limited
distribution to the brain. Recently, it has been shown that these two drug
transporters cooperate at the BBB and brain penetration of dual substrates
increase significantly only when both are absent, e.g., in the
Mdr1a/1b-/-Bcrp1-/- mice. The present study uses the brain penetration of
sorafenib to investigate these findings and attempts to explain the mechanistic
basis of this cooperation with a simple theory based on affinity and capacity
dependent carrier-mediated transport. The brain efflux index method, combined
with the organotypic brain slices, were used to determine the net contribution of
P-gp and BCRP to the total clearance of sorafenib out of the brain and show that
its efflux at the BBB is mediated primarily by BCRP. Sorafenib clearance out of
the brain decreased 2-fold in the Bcrp1-/- mice and 2.5-fold in the
Mdr1a/1b-/-Bcrp1-/- mice. Clearance out of brain when P-gp was absent did not
change significantly compared to wild-type. We also investigated the expression
of P-gp and BCRP in the genetic knockout animals and saw no differences in either
P-gp or BCRP in the transporter deficient mice compared to the wild-type mice. In
conclusion, this study explains the cooperation of P-gp and BCRP by analysis of
the efflux clearance of sorafenib and correlating it to the 'mechanisms' that
determine the clearance, i.e., affinity and capacity.

PMID: 22335402 [PubMed - as supplied by publisher]