Intravenous lipid emulsion is presented as a lifesaving treatment of
lipophilic drug intoxications (12,14,15). ‘Lipid sink’ theory is the
most emphasized theory explaining how ILE works, was first introduced by
Weinberg et al. in 1998 (12). According to this theory, by administering
ILE intravenously, expansion in the lipid compartment of blood is
provided. The drug, which is at a toxic level, first migrates to the
aqueous part of the plasma and then to the lipid compartment, which is
subsequently dissolved, thereby reducing the amount of active drug in
the target tissue. Because of these properties, it is suggested that
lipid emulsions trap oil-soluble toxic substances in circulation and
cause to sink in the emulsion (12). Another theory is the ‘Ion Channel
Theory’. In this theory, it has been suggested that free fatty acids in
lipid therapy have been shown to activate voltage-gated calcium channels
and increases intracellular calcium level. These mechanism has positive
inotropic effect on myocytes (21–23). The other theory is that the
lipid emulsion is used as a source of cardiac energy. Fatty acids are
used for myocardial ATP synthesis in normal resting cardiac tissue (24).
In recent literature it is said that this cleaning effect is not only a
static waste effect, but also a dynamic shuttle effect (14). The lipid
compartment in the blood creates a shuttle effect by removing lipophilic
drugs from organs. In this way, organs with high blood flow are
detoxified from the drugs. Although the mechanism of action is not fully
understood, it is thought that the effectiveness of ILE in the
intoxication of local anesthetic and other lipophilic drugs depends on
the combined effects of these mechanisms (15).
Based on these theories we had investigated the effectiveness of ILE in
reversing the unwanted effects of pioglitazone at a single dose of ½
LD50. We had used histopathological evaluation in order to test and
compare the changes. Our results showed that toxic effects may occur in
the liver and kidney in an acute intoxication model with a given dose of
pioglitazone, and intralipid emulsion therapy is not fully effective in
reversing these toxic effects. Besides, ILE itself may have nephrotoxic
effects.
In the literature, studies and case reports about pioglitazone generally
showed that it has hepatotoxic effects both in acute or subacute
overdoses which is also consistent with our study. Farley Hills et al.
reported a patient who developed and died of acute hepatitis due to
pioglitazone use (25). May et al. reported a case in which increased
liver transaminase levels and histopathological changes in the liver due
to pioglitazone use and these effects improved after discontinuing
pioglitazone (26). Chase et al. reported a patient presenting with
fulminant liver failure due to pioglitazone use and liver failure was
recovered after discontinuing the drug (27). The mechanism for
hepatotoxicity it is thought to be related with inhibition of ATP
production by pioglitazone which causes cytotoxicity and oxidative
stress. Reactive metabolite formation and hepatocyte mitochondrial
dysfunction may occur by this way (28). On the contrary, El Gawly et al.
reached a different result with their experimental studies. In their
study, streptozotocin was used to generate diabetes mellitus in the
animal model. For the pioglitazone dose, the maximum daily dose for
humans, 4mg/kg, was used. The study showed that pioglitazone may have
positive effects on the liver (29). This different result might be
related with low dose of pioglitazone in this study. Our result showed a
significant hepatotoxicity with ½ LD50 dose of pioglitazone. The answer
to the question of whether ILE can reverse this toxic effect was
negative.
Elimination of pioglitazone and its excretion of metabolites are mainly
from the liver. Renal clearance of pioglitazone is very low (30).
Chinnam et al. showed that the acute toxicity of the pioglitazone in an
animal model caused congestion in the kidney besides changes in the
liver and heart tissue (8). In the study of Sai Elshama et al.,
subchronic toxicity was created for 90 days in an animal model of
diabetes mellitus. They showed similar results with the Chinnam et al in
the kidney tissues of the subjects (9). Our results about renal toxicity
are consistent with the literature. ILE did not have a positive effect
on reversing the toxic effects of pioglitazone on kidney according to
our results. Besides, we observed toxic effects of ILE on the kidney
cells in the 2nd group which we had administered only
ILE. Even if the underlying mechanism is not fully understood studies
showing that ILE itself is renal toxic, our findings are also consistent
with the literature (31,32).
Some experimental studies also showed that pioglitazone also has toxic
effects on heart tissue. Yang et al. reported that pioglitazone causes
cardiac muscle hypertrophy and subsequent ventricular hypertrophy in an
animal model. They gave daily pioglitazone at a dose of 200 and 540
mg/kg/day for 12 weeks (33). Therefore, we had also investigated the
histopathological changes on our subjects’ heart tissues. Although some
changes observed in the 3rd and 4thgroup which we had administered pioglitazone, those were not found
statistically significant. We thought that more long-term use might be
needed in order to see a significant cardiac muscle hypertrophy. ILE did
not change the heart tissue evaluations in our study.