M. Yabuki et al., Local thrombus formation in the site of intravenous injection of chlorpromazine: Possible colloid-osmotic lysis of the local endothelial cells, BIOL PHAR B, 23(8), 2000, pp. 957-961
Since amphiphilic drugs are known to interact with biomembranes, we investi
gated Local vessel damage and thrombosis which might be brought about by in
travenous dosing using chlorpromazine (CPZ) as a representative compound. C
PZ-induced hemolysis was suppressed by an increase in sucrose concentration
in the medium, characterizing this hemolysis to be colloid-osmotic lysis,
which includes the enhancement of membrane phospholipid fluidity and conseq
uent small pore formation in the membranes. This was supported by the obser
vation that hemolysis by filipin, not featuring the stage of small pore for
mation, was not affected by sucrose. [C-14]Glucose-entrapping liposomes wer
e degraded by CPZ, and this degradation was enhanced by an increase in the
intravesicle glucose concentration. These results indicated that the compou
nd could induce colloid-osmotic lysis in erythrocytes and artificial membra
ne vesicles, CPZ also injured cultured porcine aortic endothelial cells (PA
EC), as evidenced by lactate dehydrogenase (LDH) leakage, This injury was a
lso suppressed by increase in sucrose concentration in the medium, suggesti
ng that colloid-osmotic lysis again occurred. When rats were intravenously
injected with CPZ, local endothelial cell (EC) injury and associated thromb
us formation were observed, suggesting that CPZ's action was also evident i
n vivo. To our knowledge, this is the first finding which suggests that an
intravenously dosed amphiphilic drug can injure local ECs based on a colloi
d-osmotic lysis mechanism leading to thrombosis.