Abstract

Purpose: To conduct a comprehensive evaluation of methods for calculation of tissue/plasma partition coefficients with a focus on correct prediction of volume of distribution and recommendation for a general approach to Kp calculations.

Methods: Kps were calculated by multiple methods for a set of about 80 drugs for which the experimentally determined values in rat were reported in the literature. These included the methods developed by Poulin & Theil [Poulin 2001] and the methods of Rodgers & Rowland [Rodgers 2007], as well as with a correction to the Poulin & Theil method described by Berezhkovskiy [Berezhkovskiy 2004]. In addition, a modified Rodgers & Rowland equation, developed by Simulations Plus, Inc. was included in the comparison.

Results: Among the published approaches, the equations derived by Rodgers and Rowland provided better general predictions for tissue/plasma partition coefficients for the compounds with low to moderate lipophilicity. However, the approach of using different equations for strong bases and for neutrals, acids and weak bases with a hard cutoff at base pKa = 7, as suggested by Rodgers and Rowland, puts a lot of emphasis on the very accurate prediction and measurement of pKa. It also creates a discontinuity in the Kp vs. pKa relationship, which can hardly be physiologically explained. We have modified the Rodgers and Rowland approach by developing a single equation which can be used for all compounds. This approach results in continuous transition of tissue binding from neutrals and weak bases to strong bases.

Conclusions: Our modified Rodgers and Rowland equation accounts for a more mechanistic description of drug binding to individual tissue components. Based on a more physiological explanation of drug binding to individual tissue components, it provides a smooth transition of calculated Kp from weak and moderate bases to strong bases. As a result, possible small errors in prediction or measurement of pKas will have smaller effect on the accuracy of Kp prediction.

American Association of Pharmaceutical Scientists (AAPS), November 17-19, 2008, Atlanta, GA

By Viera Lukacova, N. J. Parrott,  T. Lavè, Grace Fraczkiewicz, Michael B. Bolger