ELSEVIER International Journal of Pharmaceutics 145 (1996) 9 16 international joumai of pharmaceutics Brain/blood distribution described by a combination of partition coefficient and molecular mass Roman Kaliszan*, Michat Markuszewski Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdahsk, Gen. J. Hallera 107, Gdahsk 80-416, Poland Received 14 June 1996; accepted 19 August 1996 Abstract Limited performance of the octanol-water partition coefficient has been known in predicting the brain/blood equilibrium distribution ratio. There have been reports that predictive ability of the in vitro partition parameters increases after the introduction to regression of a correction term reflecting bulkiness of the compounds. Here a rationalization for such observations has been proposed by considering the brain/blood and the octanol-water distribution as composed of a part determined by polarity of a compound and another part determined by its nonspecific, dispersive properties. The model proposed was shown theoretically to apply to the four available representative sets of brain/blood distribution data. Instead of a search for an in vitro partition system precisely mimicking the brain/blood distribution equilibrium a model is recommended by a combination of standard partition parameters with a molecular bulkiness descriptor. Copyright © 1996 Elsevier Science B.V. Keywords: Brain/blood distribution; Bulkiness parameters; Log P; Partition coefficients; Polarity parameters; Quanti- tative structure-activity relationships (QSAR) I. Introduction Convenient and reliable methods of prediction of the equilibrium distribution of xenobiotics be- tween blood and brain are highly desired. As yet the attempts to correlate cerebrovascular perme- ability to the octanol-water partition coefficient * Corresponding author. (P) cannot be called fully successful. Correlation of that kind was graphically presented by Rapo- port et al. (1979). The observed marked devia- tions from the linear regression line have been explained by the authors as effects of size, steric and electronic parameters, and possibly of specific interaction with cell membranes. Better linear cor- relations (correlation coefficient r ranging from 0.85 to 0.91) were reported by Levin (1980) and by Cornford et al. (1982). Those authors assumed 0378-5173/96/$15.00 Copyright © 1996 Elsevier Science B.V. All rights reserved PII S0378-5173(96)04712-6