Etomoxir
An irreversible carnitine palmitoyltransferase-1 (CPT-1) inhibitor developed as a metabolic drug for diabetes and heart failure. Clinical development was halted after unacceptable hepatotoxicity. It is now used almost exclusively as a laboratory tool to block fatty-acid oxidation in research.
01 Overview
Etomoxir irreversibly inhibits CPT-1, the enzyme that shuttles long-chain fatty acids into mitochondria, thereby blocking beta-oxidation and forcing reliance on glucose. It was investigated for type 2 diabetes and chronic heart failure on the metabolic-shift rationale shared with perhexiline and trimetazidine.
The ERGO trial in heart failure was terminated early because of hepatotoxicity (elevated transaminases), ending clinical development. Etomoxir persists as a widely used experimental probe of fatty-acid oxidation in immunometabolism and cancer-metabolism research, though even that use is complicated by off-target effects at high concentrations. It has no approved human indication.
02 Mechanism
Irreversibly inhibits carnitine palmitoyltransferase-1 (CPT-1), blocking mitochondrial fatty-acid uptake and beta-oxidation, shifting metabolism toward glucose.
03 Dosing
| Tier | Dose | Route | Notes |
|---|---|---|---|
| Historic trial dose | 80 mg/day | Oral | Dose used in the terminated ERGO heart-failure trial; not a recommendation. |
04 Effects
| Effect | Magnitude | Evidence | |
|---|---|---|---|
| Blocks fatty-acid oxidationReliably suppresses beta-oxidation, the basis for its use as a laboratory tool. | Preclinical | ||
| Metabolic shift to glucose oxidationPreclinically improves cardiac efficiency, but human benefit was never established. | Preclinical |
05 Side effects
| Effect | Severity | Frequency | Evidence | Countermeasures |
|---|---|---|---|---|
| Cardiac hypertrophy (preclinical)Animal studies raised concern for maladaptive cardiac hypertrophy with chronic CPT-1 blockade. | Moderate | Preclinical signal | Preclinical | |
| HepatotoxicityElevated liver transaminases led to early termination of the ERGO trial. | Severe | Trial-terminating | Clinical |