Blood-brain barrier transport and protein binding of flumazenil and iomazenil in the rat: Implications for neuroreceptor studies

The calculated fraction of receptor ligands available for blood-brain barri er passage in vivo (f(avail)) may differ from in vitro (f(eq)) measurements . This study evaluates the protein-ligand interaction for iomazenil and flu mazenil in rats by comparing f(eq) and f(avail). Repeated measurements of b lood-brain barrier permeability for two benzodiazepine antagonists were per formed in 44 rats by the double-indicator technique. Cerebral blood flow wa s measured by intracarotid Xe-injection. The apparent permeability-surface product (PSapp) was measured while CBF or bolus composition was changed. Co mparison of PSapp obtained in the absence and presence of 5% albumin in the injectate yielded f(avail) whereas f(eq) was measured by equilibrium dialy sis. Iomazenil and flumazenil f(avail) was 62% and 82%, respectively, where as f(eq) was significantly lower, 42% and 61%. The PSapp for iomazenil and flumazenil increased significantly by 89% and 161% after relative CBF incre ases of 259% and 201%, respectively. The results demonstrate that applicati on of f(eq) in neuroreceptor studies underestimates the plasma input functi on to the brain. Model simulations render possible that the differences bet ween f(avail) and f(eq) as well as the effect of CBF on PSapp can be caused by capillary heterogeneity.