M. Hamdan et al., Inhibition of mitochondrial carnitine palmitoyltransferase-1 by a trimetazidine derivative, S-15176, PHARMAC RES, 44(2), 2001, pp. 99-104
The purpose of this study was to investigate the possible effect of the tri
metazidine derivative S-15176 on carnitine palmitoyltransferase1 (CPT-1) ac
tivity in rat heart and liver mitochondria. S-15176 was compared with the o
ther antianginal agents amiodarone, perhexiline and trimetazidine, which do
not show any hemodynamic effects and which are believed to exert their eff
ects by switching the cellular metabolism towards glucose utilization at th
e expense of lipid metabolism, increasing the yield of oxygen utilization.
S-15176 inhibited CPT-1 in vitro and was more effective in heart (IC50 = 16
.8 muM) than in liver (50.8 +/- 3.0 muM). In the heart, its was less effect
ive than the physiological inhibitor malonyl-CoA (IC50 = 2.1 muM), but it w
as more potent than amiodarone (IC50 = 140 muM). Kinetic experiments demons
trated a non-competitive inhibition of CPT-1 by S-15176 indicating that the
two compounds did not share the same site of action. CPT-1 inhibition was
also obvious ex vivo, in heart and liver tissues, after a 2 week treatment
with S-15176. This inhibitory effect may shift heart and liver metabolism f
rom fatty acid to glucose oxidation and contribute to the anti-ischemic eff
ects of the drug. (C) 2001 Academic Press.