The distribution of negatively charged liposomes in rats with normal or depressed function of the liver RES was examined. RES activity was determined by the uptake of the sheep red blood cells (SRBC). Whereas pretreatment with colloidal carbon or dextran sulphate drastically diminishes the SRBC uptake by the liver, the liposome uptake is decreased by 12-15% only. In the spleen, such pretreatment boosts the SRBC uptake five- to sixfold, whereas liposome uptake was decreased by about 50%. This indicates that phagocytosis by the RES is only of several liposome-cell interactions. Consequently, the suppression of the RES function is of no practical use when attempting to suppress the preferential liposome uptake by the liver and spleen.
Gabexate mesilate (FOY, ethyl-p-(6-guanidino-hexanoyl-oxy)-benzoate-methansulfonate), camostate (N,N-dimethyl-carb-amoylmethyl-4-(guanidinobenzoyloxy)-phenyl-acet ate) methansulfonate and aprotinine (Trasylol) were tested for possible inhibition of phospholipase A2. Gabexate mesilate at a concentration of 5 x 10(-4) mol/l and camostate at a concentration of 10(-3) mol/l caused a 50% reduction in enzyme activity. There was almost no inhibition by aprotinine at clinical doses; 40 million KIU/l were necessary to reduce phospholipase A2 activity by 20%. From the therapeutic dose (4,000 mg/day per i.v. infusion) and the half-life of gabexate mesilate in blood circulation (1 min) it can be calculated that the in vitro concentration of gabexate mesilate is only 10(-6) to 10(-7) mol/l. Under these conditions gabexate mesilate cannot diminish the in vivo enzyme activity of phospholipase A2.
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