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

Abstract

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.

Drug Distribution into Peripheral Nerve

“…The K p,uu values of haloperidol were generally higher than unity (2.34-6.42), likely due to experimental variability. The steady-state K p,uu,br value of haloperidol was reported previously to be 1.77 in rats (Summerfield et al, 2016).…”

“…The transport mechanisms of compounds across tissue barriers can be inferred from the K p,uu values at steady state. The compounds' K p,uu values below 1 suggest carrier-mediated efflux and/or low passive permeability and above 1 indicate active influx, whereas the K p,uu values equal to unity represent passive permeability and/or balanced active efflux/influx processes (Hammarlund-Udenaes et al, 2008;Rankovic, 2015;Summerfield et al, 2016). As compared with BBB penetration, the physicochemical and transport properties governing the drug distribution into peripheral nerves remain largely unexplored.…”

Applicability of free drug hypothesis to drugs with good membrane permeability that are not efflux transporter substrates: A microdialysis study in rats

“…These results suggest that sumatriptan is a P‐gp substrate. The notion that sumatriptan is a P‐gp substrate is supported by a rat study conducted by Summerfield et al 20 In their rat study, the ER value of sumatriptan obtained from MDR1‐MDCK assay was reported to be 2.9, and the steady‐state unbound concentrations in the brain was about 20‐fold lower than that in plasma.…”

“…Supplemental kinetic study in rodents may facilitate accurate identification of efflux transporters. Recently, it has been reported that the unbound concentrations of several drugs in the brain were greater than in plasma, suggesting the involvement of active influx transporters in brain uptake 20,57 . Conceivably, drugs that are substrates of influx transporters are also not expected to follow the free drug hypothesis.…”

“…For example, Summerfiel et al conducted a study to compare plasma unbound drug concentrations with brain unbound drug concentrations for more than 50 compounds 20 . In this study, the plasma unbound concentrations were calculated from the product of the plasma unbound fraction and plasma total concentration, while the brain free concentrations were calculated from the product of the brain unbound fraction and brain total concentration.…”