Examining the Uptake of Central Nervous System Drugs and Candidates across the Blood-Brain Barrier.

Assessing the equilibration of the unbound drug concentrations across the blood-brain barrier (Kp,uu) has progressively replaced the partition coefficient based on the ratio of the total concentration in brain tissue to blood (Kp). Here, in vivo brain distribution studies were performed on a set of central nervous system (CNS)-targeted compounds in both rats and P-glycoprotein (P-gp) genetic knockout mice. Several CNS drugs are characterized by Kp,uu values greater than unity, inferring facilitated uptake across the rodent blood-brain barrier (BBB). Examples are shown in which Kp,uu also increases above unity on knockout of P-gp, highlighting the composite nature of this parameter with respect to facilitated BBB uptake, efflux, and passive diffusion. Several molecules with high Kp,uu values share common structural elements, whereas uptake across the BBB appears more prevalent in the CNS-targeted drug set than the chemical templates being generated within the current lead optimization paradigm. Challenges for identifying high Kp,uu compounds are discussed in the context of acute versus steady-state data and cross-species differences. Evidently, there is a need for better predictive models of human brain Kp,uu.