A Physiologically-Based Pharmacokinetic Model of the Brain Considering Regional Lipid Variance.

Modeling and simulation of the central nervous system provides a tool for understanding and predicting the distribution of small molecules throughout the brain tissue and cerebral spinal fluid (CSF), and these efforts often rely on empirical data to make predictions of distributions to move toward a better understanding. A physiologically based pharmacokinetic model presented here incorporates multiple means of drug distribution to assemble a model for understanding potential factors that may determine the distribution of drugs across various regions of the brain, including both intra- and extracellular regions. Two classes of parameters are presented. The first concerns regional gross anatomic variability of the brain; the second concerns estimation of unbound fractions of drugs using know membrane phospholipid heterogeneity derived from regional lipid content. The model was then tested by comparing its outcomes to data from published human pharmacokinetic studies of acetaminophen, morphine, and phenytoin. The alignment of model predictions in the plasma, CSF, and tissue concentrations with the published data from studies of those three drugs suggests that the model can be a template for identifying drug localization in the brain. Clearly, knowledge of differentiated drug distribution in the brain is a requisite step in postulating pharmacodynamic and certain disease mechanisms. SIGNIFICANCE STATEMENT: This study concerns the application of heterogenous lipid distribution in brain tissue to predict regional variations in drug distribution in the brain via a mathematical model, thus expanding upon the current understanding of mechanisms of drug distribution in the central nervous system.