The brain as a protected efficacy and/or toxicity compartment

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Distribution of selected drug transporters at the BBB. ABC transporters are ATP-driven xenobiotic efflux pumps that can be highly polyspecific (P-glycoprotein is an extreme example), with overlapping substrate specificities that are briefly outlined for each in the boxes. There is considerable controversy over the localization of essentially all ABC transporters in brain capillaries [1,6]. It is likely that species differences in protein expression levels and cellular transporter distribution, as well as differences in detection techniques across laboratories, underlie many of the conflicts that permeate the literature. Nevertheless, when expressed on the luminal plasma membrane, ABC transporters provide an active, structure-sensitive barrier to drugs within the vascular space. Other transporters shown are members of the SLC superfamily and handle primarily organic anions and weak organic acids. Substrates for these transporters include some drugs, such as nonsteroidal anti-inflammatory drugs, as well as drug metabolites and waste products of normal CNS metabolism. They, along with luminal ABC transporters, provide a two-stage system for active and efficient excretion of potentially toxic chemicals and metabolites from the CNS.

(Figure taken from Trends in Pharmacological Sciences Vol.31 No.6)

The brain has for a long time been recognized as a very well protected organ. Chemically, the brain is isolated from the circulation by means of a very tight blood-brain barrier (BBB), first described by Stern in 1921. This BBB consists of very tightly stitched together endothelial junctions which restrict free movement of molecules from the circulation into the interstitial fluid of the brain. The capillaries are themselves encased by a thick basement membrane and the enveloping foot processes of the astrocytes.

It was thought for a long time that this barrier allowed small and lipophilic molecules to passively diffuse across, and that specific transporters mediated essential solutes such as glucose etc. This model however has been challenged by the recognition that few molecules, no matter how small or lipophilic, would diffuse across membranes without the assistance of some transporter protein. Even water required the assistance of aquaporins. The BBB is now recognized as a very sophisticated and metabolically dynamic membrane populated by not only transporter proteins but also CYP450 enzymes.

These functions of the BBB have recently been reviewed and it is worthwhile reading up on these. The following one is a recommended as it discusses also the regulation of transporters at the BBB:
Miller, D. Trends in Pharmacological Sciences 31 (2010) 246–254 (from where the above figure has been borrowed).

The article concludes:
It is now clear from studies with animal models and with patient samples that the expression and activity of P-glycoprotein and other ABC transporters at the BBB can be moving targets, affected by genetics, disease, pharmacotherapy and diet. Indeed, we are rapidly adding to maps of the signals and signaling pathways involved with a view to improving both CNS protection and the delivery of small-molecule drugs to the brain. Thus, an understanding of signaling could provide opportunities to both selectively fine tune barrier function up or down and to begin to identify the barrier-based and external factors that contribute to patient-to-patient variability in response to CNS-acting drugs. Although we are rapidly developing a very detailed picture of signaling to ABC transporters in animal models, it is still not clear to what extent these pathways operate in humans. An understanding of transporter function and regulation at the human BBB is critical before we can determine to what extent signaling can be manipulated to improve drug delivery to the CNS and to enhance neuroprotection.

It should however, also be noted that the BBB is not the only barrier that exists in the brain. It is probably the main barrier for drugs which act on surface receptors on neuronal membranes. But for drugs which act intracellularly, there is yet another barrier which exists at the cell (neurones or astrocytes) membranes. Furthermore, it is far from clear if the BBB is a uniform barrier throughout the brain. It is possible that the population of transporters may have regional differences.

Because of the existence of these barriers to the movement of drug molecules, we must be careful of trying to extrapolate too much from plasma concentrations of drugs acting on the CNS. There is often a significant dichotomy between the plasma pharmacokinetics of drug and what is actually happening not only in the brain but more specifically, intracellular mechanisms in the brain.

Deciphering the efficacy-toxicity profiles of CNS drugs become a complex exercise when efficacy is expected in the CNS while toxicity may be manifest in another tissue protected by a different population of receptors. It becomes even more perplexing when one considers that these populations of transporters in efficacy and toxicity compartments can be modulated differently by environmental and epigenetic mechanisms over time as well as between individuals.