| Penetration of anti-HIV1 agents to the CNS is reported to be low. The blood-brain barrier with its anatomical and functional barriers is considered to be responsible for the low penetration of therapeutic agents. Efflux transport proteins belonging to the ATP-binding cassette (ABC) superfamily, such as P-gp, BCRP and the MRPs have been localized at the apical blood-facing membrane of the microvessel endothelial cells and are likely to contribute to the functional constituent of the blood-brain barrier. The primary objective of this work was to evaluate the role of the efflux transport protein BCRP in the CNS penetration of anti-HIV1 nucleosides. We evaluated the interaction of anti-HIV nucleosides in vitro and in vivo. We demonstrated that the nucleoside analogs zidovudine, abacavir, zalcitabine, lamivudine, didanosine and stavudine are substrates for BCRP-mediated transport. In vivo examination indicated that deletion of Bcrp1 has little influence on the pharmacokinetics or brain penetration of zidovudine. However, for abacavir, deletion of Bcrp1 reduces plasma exposure and enhances brain penetration. These findings suggest that Bcrp1 does not influence the CNS distribution of zidovudine but may play a minor role in limiting the CNS distribution abacavir. The use of selective and non-selective inhibitors revealed that the brain penetration of abacavir is dependent on P-glycoprotein mediated efflux. In addition, during our studies of substrate-inhibitor-transporter interactions in vitro, we observed interactions of substrate molecules with BCRP that involve multiple binding regions in the protein.;The influence of BCRP on the disposition of nucleoside analogs used in the treatment of HIV needs to be fully evaluated. The existence of multiple binding site interactions, nonlinear expression-function relationships and lack of in vitro and in vivo correlations highlight the need for the careful design and interpretation of in vitro studies to examine transporter-mediated interactions. |
