RATIONALE FOR INFLUX ENHANCEMENT VERSUS EFFLUX BLOCKADE TO INCREASE DRUG EXPOSURE TO THE BRAIN

Various methods of optimizing brain exposure to polar compounds have b een examined. However, direct comparisons of the potential efficacy of these methods have not been forthcoming. The present study utilized a mathematical approach to compare the efficacy of two pharmacologic me thods of improving brain drug distribution: uptake enhancement and eff lux blockade. In the present simulation study, the pharmacokinetics of a hypothetical marker and modifier were described by differential equ ations. The relationship between modifier effect on marker uptake into , or efflux from, the brain and modifier concentration in serum (uptak e enhancement) or brain tissue (efflux blockade) was described by the Hill equation. Uptake enhancement increased both the rate and extent o f marker penetration into the brain. Efflux blockade resulted in delay ed attainment of maximum marker concentration, and prolonged marker re sidence, in brain tissue. Under all conditions and doses examined, upt ake enhancement was more effective than efflux blockade in maximizing brain tissue exposure to the marker. Although development of agents th at enhance uptake of polar compounds may be Limited by the potential d eleterious effects of blood-brain barrier disruption, use of this appr oach in theory could represent a significant advancement in the treatm ent of brain disorders. (C) 1998 John Wiley & Sons, Ltd.