A biomimetic chromatographic and computational approach to the  rate of drug passage through the Blood-Brain Barrier

Compounds’ affinity for the CNS is expressed using different parameters, including:

i) log BB (the ratio of the total, equilibrium  drug concentration in the brain to that in blood)

ii) log PS expressed in  [mL/min/g brain] and obtained via in situ brain perfusion studies using the Renkin-Crone equation: PS = -F∙ln (1-K_in/F), where F is the cerebral blood or perfusion flow rate, K_in = (Q_br/Q_pf)/T is the unidirectional transfer constant, Q_br is the concentration, corrected for the vascular volume, of compound in the brain, Q_pf is the concentration of a compound in the perfusion fluid, and T is the perfusion time

iii) the unbound brain-to-plasma concentration ratio (K_p,uu,brain) and the unbound CSF (cerebrospinal fluid)-to-plasma concentration ratio (K_p,uu,CSF).

In this study, log PS was predicted for a group of 21 drugs based on experimental reference data. It was established that log PS is related to the Immobilized Artificial Membrane (IAM) chromatographic retention parameter obtained with 100% aqueous mobile phases, log k_IAM^w – for the correlation between log PS and log k_IAM^w, Pearson’s R = 0.74 (vs. R = 0.51 for the relationship between log PS and the Micellar Liquid Chromatographic retention data obtained using sodium dodecyl sulfate-based micellar mobile phases). It seemed therefore likely that log PS can be predicted using a combination of IAM chromatographic and calculated descriptors. A model of log PS proposed in this study involved log k_IAM^w and computational descriptors TPSA (Topological Polar Surface Area), Mw (Molecular Weight), and (N+O) (the total count of N and O atoms). The coefficients for TPSA and M_w are negative, suggesting that excessive polarity and molecular size reduce the rate of BBB passage.