Rationale for influx enhancement versus efflux blockade to increase drug exposure to the brain

Various methods of optimizing brain exposure to polar compounds have been 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 methods of improving brain drug distribution: uptake enhancement and efflux blockade. In the present simulation study, the pharmacokinetics of a hypothetical marker and modifier were described by differential equations. The relationship between modifier effect on marker uptake into, or efflux from, the brain and modifier concentration in serum (uptake enhancement) or brain tissue (efflux blockade) was described by the Hill equation. Uptake enhancement increased both the rate and extent of marker penetration into the brain. Efflux blockade resulted in delayed attainment of maximum marker concentration, and prolonged marker residence, in brain tissue. Under all conditions and doses examined, uptake enhancement was more effective than efflux blockade in maximizing brain tissue exposure to the marker. Although development of agents that enhance uptake of polar compounds may be limited by the potential deleterious effects of blood-brain barrier disruption, use of this approach in theory could represent a significant advancement in the treatment of brain disorders.