Correlation of partitioning of nitroimidazoles in the n-octanol/saline and liposome systems with pharmacokinetic parameters and quantitative structure-activity relationships (QSAR).
The partitioning of a series of nine nitroimidazole drugs in liposomes (log Km) of various compositions has been determined and compared to their partitioning in the n-octanol/saline system (log K) at 30 degrees C. The log Km 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 Km 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 greater than 0.9 when log Km was used but less than 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.
Betageri
G V
GV
National Institute of Health, Rockville Pike, Maryland 20892.
Rogers
J A
JA
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D007928:Lethal Dose 50; D008081:Liposomes / Q000032:analysis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D009593:Nitroimidazoles / Q000032:analysis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000442:Octanols / Q000032:analysis; D012965:Sodium Chloride; D012995:Solubility; D013329:Structure-Activity Relationship
D008081:Liposomes; D009593:Nitroimidazoles; D000442:Octanols; D012965:Sodium Chloride