6-mercaptopurine (6-MP) has been used clinically for 40 years to maintain remission in patients with
acute lymphoblastic leukemia (ALL). However, central nervous system (CNS) relapses frequently occur in patients with ALL who continuously receive anticancer drugs, including 6-MP, during remission maintenance
therapy. The cause of such CNS relapse is not well understood. One possible reason may involve the restricted distribution of 6-MP in the brain. This study, therefore, investigates the blood-brain barrier (BBB) transport which largely regulates 6-MP distribution in the brain using a quantitative microdialysis technique and centers on the efflux transport of 6-MP across the BBB. The brain tissue, cerebrospinal fluid (CSF), or hippocampal interstitial fluid (ISF) concentration of 6-MP was very low compared with the unbound plasma concentration, suggesting that 6-MP distribution in the brain is highly restricted. Kinetic analyses of this BBB transport showed that the efflux clearance from brain ISF to plasma across the BBB (CLout) is approximately 20-times greater than the influx clearance from plasma to brain (CLin). The CLout was significantly reduced by 1mM
N-ethylmaleimide (NEM), a sulfhydryl-modifying agent, suggesting the participation of
transport protein in the efflux of 6-MP across the BBB. In addition, efflux transport was inhibited by an intracerebral infusion of
probenecid (1.5 mM),
p-aminohippuric acid (PAH, 3.0 mM),
benzoate (3.6 mM), or
salicylate (3.7 mM) administered through a microdialysis probe, but neither
choline (0.8 mM) nor
tetraethylammonium (
TEA, 0.7 mM) had any effect. These data suggest that the restricted 6-MP brain distribution may be ascribed to efficient efflux from the brain, possibly via both the organic
anion transport system, shared with
probenecid and PAH, and the monocarboxylic
acid transport system, shared with
benzoate and
salicylate.