Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone

Biochem Pharmacol. 1996 Jul 26;52(2):273-80. doi: 10.1016/0006-2952(96)00204-3.


The mechanism of the anti-anginal effect of perhexiline is unclear but appears to involve a shift in cardiac metabolism from utilization of fatty acid to that of carbohydrate. We tested the hypothesis that perhexiline inhibits the enzyme carnitine palmitoyltransferase-1 (CPT-1), which controls access of long chain fatty acids to the mitochondrial site of beta-oxidation. Perhexiline produced a concentration-dependent inhibition of CPT-1 in rat cardiac and hepatic mitochondria in vitro, with half-maximal inhibition (IC50) at 77 and 148 mumol/L, respectively. Amiodarone, another drug with anti-anginal properties, also inhibited cardiac CPT-1 (IC50 = 228 mumol/L). The rank order of potency for inhibition was malonyl-CoA > 4-hydroxyphenylglyoxylate (HPG) = perhexiline > amiodarone = monohydroxy-perhexiline. Kinetic analysis revealed competitive inhibition of cardiac and hepatic CPT-1 by perhexiline with respect to palmitoyl-CoA but non-competitive inhibition with respect to carnitine. Curvilinear Dixon plots generated "apparent inhibitory constant (Ki)" values for perhexiline, which indicated a greater sensitivity of the cardiac than the hepatic enzyme to inhibition by perhexiline. Perhexiline inhibition of CPT-1, unlike that of malonyl-CoA and HPG, was unaffected by pretreatment with the protease nagarse. These data establish for the first time that two agents with proven anti-anginal effects inhibit cardiac CPT-1. This action is likely to contribute to the anti-ischaemic effects of both perhexiline and amiodarone.

MeSH terms

  • Amiodarone / pharmacology*
  • Animals
  • Anti-Arrhythmia Agents / pharmacology
  • Cardiovascular Agents / pharmacology*
  • Carnitine O-Palmitoyltransferase / antagonists & inhibitors*
  • Carnitine O-Palmitoyltransferase / biosynthesis
  • Male
  • Mitochondria, Heart / enzymology*
  • Mitochondria, Liver / enzymology*
  • Perhexiline / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Subtilisins / pharmacology


  • Anti-Arrhythmia Agents
  • Cardiovascular Agents
  • Carnitine O-Palmitoyltransferase
  • Subtilisins
  • Perhexiline
  • Amiodarone