Comparison of CYP2D metabolism and hepatotoxicity of the myocardial metabolic agent perhexiline in Sprague–Dawley and Dark Agouti rats

Abstract

1. Perhexiline, a chiral anti-anginal agent, may be useful to develop new cardiovascular therapies, despite its potential hepatotoxicity.

2. This study compared Dark Agouti (DA) and Sprague–Dawley (SD) rats, as models of perhexiline’s metabolism and hepatotoxicity in humans. Rats (n = 4/group) received vehicle or 200 mg/kg/d of racemic perhexiline maleate for 8 weeks. Plasma and liver samples were collected to determine concentrations of perhexiline and its metabolites, hepatic function and histology.

3. Median (range) plasma and liver perhexiline concentrations in SD rats were 0.09 (0.04–0.13) mg/L and 5.42 (0.92–8.22) ng/mg, respectively. In comparison, DA rats showed higher (p < 0.05) plasma 0.50 (0.16–1.13) mg/L and liver 24.5 (9.40–54.7) ng/mg perhexiline concentrations, respectively, 2.5- and 3.7-fold higher cis-OH-perhexiline concentrations, respectively (p < 0.05), and lower plasma metabolic ratio (0.89 versus 1.55, p < 0.05). In both strains, the (+):(−) enantiomer ratio was 2:1. Perhexiline increased plasma LDH concentrations in DA rats (p < 0.05), but had no effect on plasma biochemistry in SD rats. Liver histology revealed lower glycogen content in perhexiline-treated SD rats (p < 0.05), but no effects on lipid content in either strain.

4. DA rats appeared more similar to humans with respect to plasma perhexiline concentrations, metabolic ratio, enantioselective disposition and biochemical changes suggestive of perhexiline-induced toxicity.

• Biotransformation
• glycogen
• lipid

Acknowledgements

We would like to thank Mr John K. Brealey from the Electron Microscope Unit, and Dr John Pierides from the Department of Surgical Pathology and Cytopathology of The Queen Elizabeth Hospital for their expertise and assistance in performing the histological analyses for this project. Mr John Licari was the recipient of a postgraduate scholarship awarded by The Queen Elizabeth Hospital Research Foundation. This work was presented in part at the 16th North American Regional meeting of the International Society of the Study of Xenobiotics, October 18--22, 2009, Baltimore, USA.

Declaration of interest

The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article.

The authors are inventors on a patent application for the use of perhexiline enantiomers, which is licensed to Heart Metabolics.