Central nervous system distribution of novel antitumor agents, pemetrexed and STI-571: Role of efflux transport systems

Pemetrexed is a novel antifolate compound and is effective against several solid tumors. As the first step to investigate its potential application in CNS tumors, the CNS distributional kinetics of pemetrexed was investigated in rats by simultaneously examining unbound pemetrexed concentrations in arterial blood and cortical extracellular fluid (ECF). HPLC methods for on-line microdialysis and offline plasma assay of pemetrexed were developed. A novel microdialysis probe was designed and validated for arterial microdialysis which proved to be advantageous in eliminating the ultrafiltration of perfusate across the probe membrane, an important criterion for establishing probe recovery, Both intravenous bolus and infusion studies showed that pemetrexed has a limited CNS distribution, The steady-state free concentration of pemetrexed in cortical ECF after intravenous infusion was approximately 10-fold less than that in plasma, and the distributional clearance out of the brain was approximately 10-fold greater than the distributional clearance into the brain after iv bolus. The data suggest the involvement of active efflux transport system in the distribution process, however, indomethacin, an established organic anion transport inhibitor, had no effect on either the brain-to-plasma AUC ratio or the steady state brain-to-plasma concentration ratio.; STI-571 targets BCR/ABL tyrosine kinase, showing high efficacy against chronic myelogenous leukemia (CML) in peripheral tissues. However, the development of resistance and CNS relapse has hindered the success of STI-571 in the treatment of CML. In this study, in vitro and in vivo experiments clearly demonstrated that STI-571 is a substrate of the efflux transporter, P-glycoprotein (P-gp), which is expressed in blood-brain barrier. The brain distribution of STI-571 is limited by P-gp and inhibition of P-gp led to a significant increase in CNS distribution of this agent.; Studies presented in this dissertation provide useful information about the transport kinetics of these novel antitumor agents and lay the foundation for future intervention to increase their CNS distribution, and therefore for more successful treatment of primary and secondary cancers in the CNS.