Enantioselectivity in the tissue distribution of perhexiline contributes to different effects on hepatic histology and peripheral neural function in rats.

Perhexiline, a chiral drug, is a potent antiischemic agent whose clinical utility is limited by hepatic and neural toxicities. It inhibits mitochondrial carnitine palmitoyltransferase-1, however, excessive inhibition predisposes toward tissue steatosis. This pilot study investigated the distribution of the two enantiomers and their toxicological potential. Dark Agouti rats (n = 4 per group) were administered vehicle or 200 mg/kg daily of racemic, (+)- or (-)-perhexiline maleate orally for 8 weeks. Plasma biochemical liver function tests and Von Frey assessments of peripheral neural function were performed. Hepatic and neuronal histology, including lipid and glycogen content, was assessed using electron microscopy. Concentrations of the perhexiline enantiomers and metabolites were quantified in plasma, liver and heart. Plasma perhexiline concentrations following administration of racemate, (+)- or (-)-enantiomer were within the mid-upper clinical therapeutic range. There was extensive uptake of both enantiomers into liver and heart, with 2.5- to 4.5-fold greater net uptake of (+)- compared to (-)-perhexiline (P < .05) when administered as pure enantiomers, but not when administered as racemate. There was no biochemical or gross histological evidence of hepatotoxicity. However, livers of animals administered (+)-perhexiline had higher lipid (P < .01) and lower glycogen (P < .05) content, compared to those administered (-)-perhexiline. Animals administered racemic perhexiline had reduced peripheral neural function (P < .05) compared to controls or animals administered (-)-perhexiline. For the same plasma concentrations, differences in tissue distribution may contribute to disparities in the effects of (+)- and (-)-perhexiline on hepatic histology and neural function.

Stereoselective handling of perhexiline: implications regarding accumulation within the human myocardium.

PURPOSE: Perhexiline is a prophylactic anti-ischaemic agent with weak calcium antagonist effect which has been increasingly utilised in the management of refractory angina. The metabolic clearance of perhexiline is modulated by CYP2D6 metaboliser status and stereoselectivity. The current study sought to (1) determine whether the acute accumulation of perhexiline in the myocardium is stereoselective and (2) investigate the relationship between duration of short-term therapy and the potential stereoselective effects of perhexiline within myocardium. METHOD: Patients (n = 129) from the active arm of a randomised controlled trial of preoperative perhexiline in cardiac surgery were treated with oral perhexiline for a median of 9 days. Correlates of atrial and ventricular concentrations of enantiomers were sought via univariate followed by multivariate analyses. RESULTS: Myocardial uptake of both (+) and (-) perhexiline was greater in ventricles than in atria, and there was more rapid clearance of (-) than (+) perhexiline. The main determinants of atrial uptake of both (+) and (-) perhexiline were the plasma concentrations [(+) perhexiline: ß = -0.256, p = 0.015; (-) perhexiline: ß = -0.347, p = 0.001] and patients' age [(+) perhexiline: ß = 0.300, p = 0.004; (-) perhexiline: ß = 0.288, p = 0.005]. Atrial uptake of (+) enantiomer also varied directly with duration of therapy (ß = 0.228, p = 0.025), while atrial uptake of (-) perhexiline varied inversely with simultaneous heart rate (ß = -0.240, p = 0.015). CONCLUSION: (1) Uptake of both perhexiline enantiomers into atrium is greater with advanced age and displays evidence of both saturability and minor stereoselectivity. (2) Atrial uptake of (-) perhexiline may selectively modulate heart rate reduction.

Steady-state pharmacokinetics of the enantiomers of perhexiline in CYP2D6 poor and extensive metabolizers administered Rac-perhexiline.

UNLABELLED: What is already known about this subject. Perhexiline (PHX) is administered as a racemic mixture and exhibits enantioselective pharmacokinetics in both poor and extensive metabolizers of CYP2D6 (PM and EM, respectively). Extensive metabolism by CYP2D6 is primarily responsible for the observed enantioselectivity in EM, but the process responsible in PM is unknown. Analysis of the steady-state plasma concentration-time profiles of the enantiomers of PHX in PM and EM was undertaken in order to elucidate the observed enantioselectivity, particularly with respect to PM. What this study adds. This is the first study to examine the steady-state plasma concentration-time profiles of the enantiomers of PHX in EM and PM over the course of an interdosing interval. The apparent oral clearance of each enantiomer was calculated from their respective AUC rather than from trough concentrations and was enantioselective in both phenotypes, with higher apparent oral clearances of (-)-than (+)-PHX. Renal clearance, calculated for EM and subsequently assumed for PM, constitutes a greater proportion of the total apparent oral clearance of each enantiomer in PM than EM, but was not enantioselective and thus unable to explain the enantioselectivity observed in PM. AIMS: To determine the steady-state pharmacokinetics of perhexiline (PHX) enantiomers over one interdosing interval in CYP2D6 extensive and poor metabolizer (EM and PM, respectively) patients administered rac-PHX. To elucidate the processes responsible for enantioselectivity, particularly in PM patients. METHODS: Blood samples were taken over one interdosing interval from six EM and two PM patients at steady-state with respect to rac-PHX metabolism. Complete urine collections were taken from five EM patients. PHX concentrations in plasma and urine were determined with enantioselective high-performance liquid chromatography methods. RESULTS: EM patients had 16- and 10-fold greater median apparent oral clearances of (+)- and (-)-PHX, respectively, than PM patients (P < 0.05 for both) and required significantly larger doses of rac-PHX (69 vs. 4.2 microg kg(-1) h(-1), P < 0.05) to maintain therapeutic concentrations in plasma. Patient phenotypes were consistent with CYP2D6 genotypes. Both groups displayed enantioselective pharmacokinetics, with higher apparent oral clearances for (-)-PHX compared with (+)-PHX, although PM patients exhibited significantly greater enantioselectivity (P < 0.05). The renal clearance of PHX enantiomers was not enantioselective and accounted for <1% of the median apparent oral clearance of each enantiomer in EM patients. Assuming the same renal clearances for PM patients accounts for approximately 9 and 4% of their median apparent oral clearances of (+)- and (-)-PHX, respectively. CONCLUSIONS: The enantioselective pharmacokinetics of PHX are primarily due to metabolism by CYP2D6 in EM patients. The mechanism responsible for the enantioselective pharmacokinetics of PHX in PM patients is unknown, but may be due to enantioselective biliary or intestinal excretion.

Perhexiline.

Perhexiline, 2-(2,2-dicyclohexylethyl)piperidine, was originally developed as an anti-anginal drug in the 1970s. Despite its success, its use diminished due to the occurrence of poorly understood side effects including neurotoxicity and hepatotoxicity in a small proportion of patients. Recently, perhexiline's mechanism of action and the molecular basis of its toxicity have been elucidated. Perhexiline reduces fatty acid metabolism through the inhibition of carnitine palmitoyltransferase, the enzyme responsible for mitochondrial uptake of long-chain fatty acids. The corresponding shift to greater carbohydrate utilization increases myocardial efficiency (work done per unit oxygen consumption) and this oxygen-sparing effect explains its antianginal efficacy. Perhexiline's side effects are attributable to high plasma concentrations occurring with standard doses in patients with impaired metabolism due to CYP2D6 mutations. Accordingly, dose modification in these poorly metabolizing patients identified through therapeutic plasma monitoring can eliminate any significant side effects. Herein we detail perhexiline's pharmacology with particular emphasis on its mechanism of action and its side effects. We discuss how therapeutic plasma monitoring has led to perhexiline's safe reintroduction into clinical practice and how recent clinical data attesting to its safety and remarkable efficacy led to a renaissance in its use in both refractory angina and chronic heart failure. Finally, we discuss the application of pharmacogenetics in combination with therapeutic plasma monitoring to potentially broaden perhexiline's use in heart failure, aortic stenosis, and other cardiac conditions.

Effect of CYP2D6 metabolizer status on the disposition of the (+) and (-) enantiomers of perhexiline in patients with myocardial ischaemia.

AIMS: This study investigated the effects of increasing doses of rac-perhexiline maleate and CYP2D6 phenotype and genotype on the pharmacokinetics of (+) and (-)-perhexiline. METHODS: In a prospective study, steady-state plasma concentrations of (+) and (-)-perhexiline were quantified in 10 CYP2D6 genotyped patients following dosing with 100 mg/day rac-perhexiline maleate, and following a subsequent dosage increase to 150 or 200 mg/day. In a retrospective study, steady-state plasma concentrations of (+) and (-)-perhexiline were obtained from 111 CYP2D6 phenotyped patients receiving rac-perhexiline maleate. RESULTS: In the prospective study, comprising one poor and nine extensive/intermediate metabolizers, the apparent oral clearance (CL/F) of both enantiomers increased with the number of functional CYP2D6 genes. In the nine extensive/intermediate metabolizers receiving the 100 mg/day dose, the median CL/F of (+)-perhexiline was lower than that of (-)-perhexiline (352.5 versus 440.6 l/day, P<0.01). Following the dosage increase, the median CL/F of both enantiomers decreased by 45.4 and 41.4%, respectively. In the retrospective study, the median (+)-/(-)-perhexiline plasma concentration ratio was lower (P<0.0001) in phenotypic extensive/intermediate (1.41) versus poor metabolizers (2.29). Median CL/F of (+) and (-)-perhexiline was 10.6 and 24.2 l/day (P<0.05), respectively, in poor metabolizers, and 184.1 and 272.0 l/day (P<0.001), respectively, in extensive/intermediate metabolizers. CONCLUSIONS: Perhexiline's pharmacokinetics exhibit significant enantioselectivity in CYP2D6 extensive/intermediate and poor metabolizers, with both enantiomers displaying polymorphic and saturable metabolism via CYP2D6. Clinical use of rac-perhexiline may be improved by developing specific enantiomer target plasma concentration ranges.

Method for the analysis of perhexiline and its hydroxy metabolite in plasma using high-performance liquid chromatography with precolumn derivatization.

A high-performance liquid chromatographic method for the analysis of perhexiline and its monohydroxy metabolite in plasma has been developed. After a simple extraction procedure, the analytes are derivatized over a 30-min period with trans-4-nitrocinnamoyl chloride. The derivatized products are monitored at 340 nm following separation on a 5-micron phenyl reversed-phase column under isocratic conditions. The limits of detection for perhexiline and its hydroxy metabolite are 0.03 and 0.02 mg/l, respectively. The between-day and within-day assay coefficients of variation for perhexiline and its hydroxy metabolite at concentrations of 0.2 and 1.0 mg/I were less than 10%. The method has proved robust and suitable for the routine monitoring of perhexiline and hydroxyperhexiline.