Correlation of Partitioning of Nitroimidazoles in the n-Octanol/Saline and Liposome Systems with Pharmacokinetic Parameters and Quantitative Structure–Activity Relationships (QSAR)

Abstract

The partitioning of a series of nine nitroimidazole drugs in liposomes (log K _m) of various compositions has been determined and compared to their partitioning in the n-octanol/saline system (log K) at 30°C. The log K _m ranged from 1.5 to 0.5 and was three- to fourfold greater than the log K; further, the linear correlation coefficient was greatest when cholesterol (CHOL)-free liposomes were used. Functional-group contributions were compared from their hydrophobic substituent constants and, except in the case of RO-07-2044 and iodoazomycin riboside, yielded negative values in all systems. Literature values of four pharmacokinetic parameters obtained in dogs and acute LD₅₀ values of the nitroimidazoles in BALB/c mice were highly correlated with log K or log K _m only in CHOL-free liposomes. Comparing the relative sensitizing effect of the nitroimidazoles in murine EMT-6 or Chinese hamster V79 tumor cell cultures and their partition coefficients, the correlation in EMT-6 cells was poor, whereas the correlation in V79 cells was >0.9 when log K _m was used but <0.6 when log K was used. Thus, the liposome model is a better predictor of nitroimidazole activity than the n-octanol/saline system and, also, it is a more flexible model for selecting the optimum conditions for QSAR studies.