title: 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.
authors: Discipline of Pharmacology, School of Medical Sciences, The University of Adelaide , Adelaide , Australia .
authors: Giovanni
authors: G
authors: Licari
authors: Andrew A
authors: AA
authors: Somogyi
authors: Robert W
authors: RW
authors: Milne
authors: Benedetta C
authors: BC
authors: Sallustio
mesh_terms: D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000818:Animals; D002317:Cardiovascular Agents / Q000378:metabolism* / Q000633:toxicity; D000072467:Cytochrome P450 Family 2; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D023421:Models, Animal; D010480:Perhexiline / Q000378:metabolism* / Q000633:toxicity; D017207:Rats, Sprague-Dawley
chemical_list: D002317:Cardiovascular Agents; D000429:Alcohol Oxidoreductases; C504568:Cyp2d1 protein, rat; D000072467:Cytochrome P450 Family 2; D010480:Perhexiline
keywords: Biotransformation; glycogen; lipid