We attempted to determine the mechanism(s) of poloxamer (P)-407-induce
d hyperlipidemia in rats by administering a lipid-lowering drug with a
known mechanism of action. Five weight-matched animals were assigned
to each of four treatment groups. Two groups received P-407 300 mg/ml
and two received saline 1 mi. One of the P-407 and one of the saline g
roups were administered nicotinic acid 100 mg/kg by intraperitoneal in
jection at 6-96 hours after blood sampling. Blood samples were collect
ed at 7 points from time zero to 120 hours and analyzed for triglyceri
de and cholesterol concentrations. The detergent produces hypertriglyc
eridemia (HTG) increasing from 53.4 +/- 7.0 mg/dl (time zero) to 4026.
9 +/- 42.1 mg/dl by 24 hours. The HTG response was significantly atten
uated by nicotinic acid (at t=24 hrs). This, however, was followed by
an average triglyceride concentration increase of 2.8-fold from 72 to
120 hours. The detergent produces a dramatic hypercholesterolemia (HCH
O), increasing cholesterol from 47.5 +/- 1.8 mg/dl to 468.5 +/- 27.9 m
g/dl by 48 hours. The HCHO was significantly affected by nicotinic aci
d administration during the accumulation phase. Nicotinic acid reduced
cholesterol concentration from 364.4 +/- 16.1 mg/dl to 276.8 +/- 16.4
mg/dl at 24 hours (p<0.05). It is a potent antilipolytic agent, limit
ing the free fatty acids available for the synthesis of triglyceride a
nd cholesterol. These data suggest that P-407 may act by stimulating t
he release of free fatty acids from the adipocyte for at least 24 hour
s after injection.