ISSN:
1573-904X
Keywords:
partitioning of nitroimidazoles
;
n-octanol/saline
;
liposomes
;
correlation analysis
;
quantitative structure–activity relationships (QSAR)
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1015931431817
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