Unbound brain compound concentration

Projecting large animal unbound brain compound concentrations... 

Figure 1 A schematic conceptualization of the three-compartment model of CNS penetration demonstrating the importance of intercompartmental unbound compound concentration relationships to target pharmacology interactions [21,22,25-28]. An exaggerated synapse is shown in the brain compartment to emphasize the locale of transmembrane proteins (squares) versus intracellular (oval) targets, and the matrix compound concentrations dictating their respective ligand-target interactions.

The lack of information conveyed by total brain concentration is indicated by studies on KA-672 [6], a lipophilic benzopyranone acetylcholinestrase inhibitor. The compound achieved total brain concentrations of 0.39 iM at a dose of 1 mg kg" equivalent to the IC50 determined in vitro (0.36 juM). Doses up to 10 mg kg were without pharmacological effect. Analysis of CSF indicated concentrations of the compound were below 0.01 juM readily explaining the lack of activity. These low concentrations are presumably due to high (unbound) free drug clearance and resultant low concentrations of free drug in the plasma (and CSF). 

The use of microdialysis has enabled unbound drug concentrations to be determined in ECF, providing another measurement of penetration across the blood-brain barrier and one more closely related to activity. A review of data obtained by microdialysis [7], showed that free drug exposure in the brain is equal to or less than free drug concentration in plasma or blood, with ratios ranging from 4% for the most polar compound (atenolol) to unity for lipophilic compounds (e.g. carbamazepine). This largely supports the similar conclusions from the CSF data shown above. This relationship is illustrated in Figure 4.4. 

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