Perhexiline Concentrations Research Articles

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.

Validation of a High-Performance Liquid Chromatography-Tandem Mass Spectrometry Method for the Determination of Perhexiline and Cis-Hydroxy-Perhexiline Plasma Concentrations.

The polymorphic nature of cytochrome P450 2D6 has made therapeutic drug monitoring of the anti-anginal agent perhexiline a compulsory step in reducing adverse events associated with plasma concentrations above the therapeutic range (0.15-0.60 mg/L). The aim of this study was to develop a high-performance liquid chromatography-mass spectrometry/mass spectrometry method for the determination of plasma perhexiline concentrations and its major metabolite cis-hydroxy-perhexiline to reduce sample extraction procedures and improve sample turnaround times. The method was validated by determining the precision and accuracy of calibrators and quality control material, comparing quality assurance program samples and patient samples measured by a previously reported liquid-liquid extraction fluorescence (FL) detection high-performance liquid chromatography method and performing matrix effects investigations. Replicates of calibrators at concentrations of 3.00 and 0.05 mg/L demonstrated imprecision of <10.8% and inaccuracy of <8.2% for perhexiline and <10.1% and <4.5% for cis-hydroxy-perhexiline, respectively. All samples measured by the 2 methods (n = 102) demonstrated Deming regression of perhexiline = 1.20 FL + 0.00 (Sy.x = 0.08, 1/slope = 0.67); cis-hydroxy-perhexiline = 1.48 FL - 0.20 (Sy.x = 0.40, 1/slope = 0.67). The assay performance was deemed acceptable and integrated into the routine therapeutic drug monitoring program of the department.

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

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.

Relationship between plasma, atrial and ventricular perhexiline concentrations in humans: insights into factors affecting myocardial uptake

Little is known regarding the steady-state uptake of drugs into the human myocardium. Perhexiline is a prophylactic anti-anginal drug which is increasingly also used in the treatment of heart failure and hypertrophic cardiomyopathy. We explored the relationship between plasma perhexiline concentrations and its uptake into the myocardium. Blood, right atrium ± left ventricle biopsies were obtained from patients treated with perhexiline for a median of 8.5 days before undergoing coronary surgery in the perhexiline arm of a randomized controlled trial. Perhexiline concentrations in plasma and heart tissue were determined by HPLC. Atrial biopsies were obtained from 94 patients and ventricular biopsies from 28 patients. The median plasma perhexiline concentration was within the therapeutic range at 0.24 mg l⁻¹ (IQR 0.12-0.44), the median atrial concentration was 6.02 mg kg⁻¹ (IQR 2.70-9.06) and median ventricular concentration was 10.0 mg kg⁻¹ (IQR 5.76-13.1). Atrial (r² = 0.76) and ventricular (r² = 0.73) perhexiline concentrations were closely and directly correlated with plasma concentrations (both P < 0.001). The median atrial : plasma ratio was 21.5 (IQR 18.1-27.1), ventricular : plasma ratio was 34.9 (IQR 24.5-55.2) and ventricular : atrial ratio was 1.67 (IQR 1.39-2.22). Using multiple regression, the best model for predicting steady-state atrial concentration included plasma perhexiline, heart rate and age (r² = 0.83). Ventricular concentrations were directly correlated with plasma perhexiline concentration and length of therapy (r² = 0.84). This study demonstrates that plasma perhexiline concentrations are predictive of myocardial drug concentrations, a major determinant of drug effect. However, net myocardial perhexiline uptake is significantly modulated by patient age, potentially via alteration of myocardial:extracardiac drug uptake.

Interaction of Terbinafine (Anti-fungal agent) with Perhexiline: A Case Report

Perhexiline is a unique anti-anginal agent that is frequently used in the treatment of chronic refractory angina. Its utility has been limited because of its complex pharmacokinetics that were only appreciated following the development of a therapeutic perhexiline assay. Perhexiline is cleared primarily via formation of mono-hydroxy metabolites (OH-perhexiline) by cytochrome P450 2D6 (CYP2D6). Drugs that are inhibitors of CYP2D6 may therefore inhibit perhexiline metabolism, increase plasma perhexiline concentration and may consequently increase the risk of toxicity. We report a case of a rise in perhexiline plasma concentration to a toxic level following the introduction of terbinafine hydrochloride; a moderate CYP2D6 inhibiting drug.

A Case Series of Concomitant Treatment of Perhexiline With Amiodarone

Concomitant treatment with amiodarone and perhsexiline has been considered to be relatively contraindicated because of the hypothetical risk of potentiated adverse effects mediated by additive inhibition of carnitine palmitoyl transferase 1. To study the prevalence of adverse effects associated with the concomitant use of perhexiline and amiodarone. A retrospective analysis of a single hospital database of patients receiving perhexiline and amiodarone between July 2009 and April 2011. Files were reviewed for short- and long-term adverse effects requiring drug cessation. Glucose concentration, gamma glutamyl transferase activity. and perhexiline blood concentrations were recorded. We identified 26 patients concomitantly treated with perhexiline and amiodarone, 20 on a long-term basis. In 6 cases, amiodarone was introduced on top of preceding perhexiline. In none of the cases were drugs stopped because of adverse effects. Although blood glucose concentrations fell significantly 48 hours postadmission to hospital, this seems to reflect the resolution of "admission hyperglycemia" rather than onset of hypoglycemia; the latter was rare (5 patients), mild, and clinically silent. In 4 patients, gamma glutamyl transferase approximately doubled. Traditionally, concomitant treatment with amiodarone and perhexiline has been considered to be relatively contraindicated on the basis of the theoretical potential for synergistic toxicity. This cohort of 26 patients received this concomitant treatment without any excess of major adverse reactions. Our findings suggest that concomitant treatment with perhexiline and amiodarone may be safe in the setting of (1) previous tolerance of either agent, and (2) titration of plasma perhexiline concentrations to guide therapy.

Enantioselective assay for the determination of perhexiline enantiomers in human plasma by liquid chromatography

Effective use of the antianginal agent perhexiline is difficult because saturable metabolism by the polymorphic cytochrome P450 2D6 (CYP2D6) isoform produces elevated plasma perhexiline concentrations that have been associated with serious hepatic and neurological toxicity. Perhexiline is marketed for therapeutic use as a racemate and there is evidence for differences in the disposition of its enantiomers. The current study describes an enantioselective HPLC-fluorescent method utilising pre-column derivatization with (R)-(-)-1-(1-napthyl)ethyl isocyanate. Following derivatization, the enantiomers are resolved on a C18 column with gradient elution using a mobile phase composed of methanol and water. The method described is suitable for the quantification of (+)- and (-)-perhexiline in human plasma following clinical doses and demonstrates sufficient sensitivity, accuracy and precision between 0.01 and 2.00 mg/l for each enantiomer, with intra-assay coefficients of variation and bias <20% at 0.01 mg/l and <10% at 2.00 mg/l, and inter-assay coefficients of variation and biases <15% at 0.03 mg/l and <10% at 0.40 and 0.75 mg/l. The application of this method to plasma samples collected from a patient treated with perhexiline revealed that (+)-perhexiline concentrations were higher than (-)-perhexiline concentrations, confirming the stereoselective disposition of perhexiline. The current study describes an enantioselective method that utilises pre-column formation of fluorescent diastereomers that are resolved on a C18 HPLC column using a gradient of methanol and water.

The influence of CYP2D6 genotype on trough plasma perhexiline and cis‐OH‐perhexiline concentrations following a standard loading regimen in patients with myocardial ischaemia

CYP2D6 protein expression is determined by the number of functional CYP2D6 alleles. It is also higher in individuals with at least one CYP2D6*2 allele. This study has investigated the effect of the number of functional CYP2D6 alleles and the influence of CYP2D6*2 alleles on plasma perhexiline concentrations in patients administered a standard loading regimen over 3 days. Eighteen patients with myocardial ischaemia who were not taking any drugs known to inhibit CYP2D6 metabolism in vivo commenced treatment with 200 mg of perhexiline twice per day. On the fourth day, blood was drawn for genotyping and the measurement of trough plasma concentrations of perhexiline and its major metabolite, cis-OH-perhexiline. The only genotypic CYP2D6 poor metabolizer had a trough plasma perhexiline concentration of 2.70 mg l-1 and no detectable cis-OH-perhexiline. The mean+/-SD trough plasma perhexiline concentration in patients with one functional allele was significantly higher (0.63+/-0.31 mg l-1, n=8, P=0.05) than in patients with two functional alleles (0.37+/-0.17 mg l-1, n=9). Conversely, the mean metabolic ratio was significantly lower in patients with one functional allele (2.90+/-1.76, P<0.01) compared with patients with two functional alleles (6.52+/-3.26). Patients with at least one CYP2D6*2 allele had a lower plasma perhexiline concentration (0.20+/-0.09 mg l-1, n=5, P<0.001) and a higher metabolic ratio (7.86+/-2.51, P<0.01) than the non-poor metabolizer patients with no CYP2D6*2 alleles (0.62+/-0.23 mg l-1 and 3.55+/-2.54, respectively, n=12). Patients with only one functional allele and not CYP2D6*2 have diminished CYP2D6 metabolic capacity for perhexiline.

Concentration‐time profile for perhexiline and hydroxyperhexiline in patients at steady state

To define inter- and intraday variability in plasma perhexiline concentrations, time-to-maximum plasma perhexiline concentration and variability in the ratio of hydroxyperhexiline to parent perhexiline concentrations over the course of the day in patients at steady state. Eight blood samples were taken over a 24-h period from 12 adult patients already taking perhexiline for the treatment of angina pectoris. These patients were assumed to be at steady state, having taken the same dose of perhexiline for more than 4 weeks and having no changes made to other drug therapy that might have affected plasma perhexiline concentrations (especially drugs that interfere with CYP2D6). Perhexiline was assayed by HPLC/FL. The percentage increase over baseline concentration was determined for each patient for both perhexiline and hydroxyperhexiline. Trough plasma perhexiline concentrations from two patients were below the limit of quantification of the assay (0.05 mg l-1) and thus were excluded from the analysis. The greatest mean percentage increase in plasma perhexiline concentration over the day was 21% (95%CI 9%, 33%, range -19% to 45%) which occurred 6 h postdose. The greatest mean percentage increase in plasma hydroxyperhexiline concentration was 10.8% (95%CI -5.3%, 26.9%, range -13% to 60%) which occurred 4 h postdose. However individual patients demonstrated > 60% intraday variability in perhexiline concentrations which was not related to the concomitant use of drugs that affect CYP2D6 activity. Changes in random plasma perhexiline concentration which are attributed to changes in concomitant drug therapy should be supported by additional kinetic data. Inter-day variability in plasma perhexiline concentration as determined by the ratio of C24 : C0 was small (mean 0.90, 95%CI 0.77, 1.03) which supports C0 as the best sampling time for perhexiline concentration monitoring. The variability in C24 : C0 for hydroxyperhexiline concentrations was smaller (mean 0.96, 95%CI 0.81, 1.11). Variability in the ratio of plasma concentrations of hydroxyperhexiline to perhexiline over the day was also small. The ratio of plasma hydroxyperhexiline to perhexiline concentration over the day fell within a narrow range for all subjects with 95% confidence intervals being < 15% for eight patients and < 25% for the remaining patient. This suggests that formation of the metabolite occurs rapidly and may be presystemic. It also supports the calculation of the hydroxyperhexiline : perhexiline ratio (in patients at steady state) on blood samples taken at any time during the dosing interval. The within-day variability in plasma perhexiline concentrations was small. While C0 is probably the best time for therapeutic drug monitoring purposes, it is not unreasonable to use samples drawn at any time during the dosing interval. The therapeutic range used in this hospital (0.15-0.6 mg l-1) was devised from earlier work using 4 h postdose blood sampling which is close to the 'peak' concentration and a mean of 16% higher than C0 in this study. This increase is probably clinically insignificant and a different C0 range is therefore not warranted.

Pharmacokinetics of the antianginal agent perhexiline: relationship between metabolic ratio and steady-state dose.

1) To develop an estimate of oral clearance (CL(Px)/F) for the antianginal agent perhexiline based on the ratio of cis-OH-perhexiline metabolite/parent perhexiline plasma concentrations at steady-state (C(OHPx,ss)/C(Px,ss)). 2) To determine whether the ratio measured in the first fortnight of treatment (C(i)(OHPx)/C(i)(Px)) may be used to guide patient dosing with perhexiline, a drug with a narrow therapeutic index, long half-life and saturable metabolism via CYP2D6. Two retrospective studies were conducted reviewing patient records and data obtained from routine monitoring of plasma perhexiline and cis-OH-perhexiline concentrations. Study 1 (n=70). At steady-state, the frequency distributions of CL(Px)/F and C(OHPx,ss)/C(Px,ss) were consistent with CYP2D6 metabolism. Putative poor metabolizers (approximately 8%) were identified by CL(Px)/F< or =50 ml min(-1) or C(OHPx,ss)/C(Px,ss)< or =0.3. A group of patients with CL(Px)/F> or =950 ml min(-1) may have been ultra-rapid metabolizers. In this group, the high CL(Px)/F values suggest extensive first-pass metabolism and poor bioavailability. In patients with therapeutic plasma perhexiline concentrations (0.15-0.60 mg l(-1)), the variability in dose appeared directly proportional to CL(Px)/F (r2=0.741, P<0.0001). Study 2 (n=23). Using C(i)(OHPx)/C(i)(Px) patients were tentatively identified as poor, extensive and ultra-rapid metabolizers, with CL(Px)/F of 23-72, 134-868 and 947-1462 ml min(-1), respectively, requiring doses of 10-25, 100-250 and 300-500 mg day(-1), respectively. The cis-OH-perhexiline/perhexiline concentration ratio may be useful for optimizing individual patient treatment with the antianginal agent perhexiline.

Cholestasis associated with the use of pravastatin sodium

celecoxib (a cytochrome P450 2D6 inhibitor) at a constant dose between Days 1 and 95, and meropenem (not a documented cytochrome P450 2D6 inhibitor) between Days 51 and 95. These patterns of administration suggest that neither of these drugs had a significant effect on perhexiline concentration. On the other hand, the laboratory evidence of a marked inhibition of perhexiline metabolism during treatment with citalopram suggests that caution is required when prescribing citalopram (or any other SSRI) for a patient taking perhexiline.

Systematic review of the efficacy and safety of perhexiline in the treatment of ischemic heart disease.

Perhexiline was introduced about 30 years ago and rapidly gained a reputation for efficacy in the management of angina pectoris. However, hepatic and neurological adverse effects associated with perhexiline administration led to a marked decline in its use. The drug was originally classified as a coronary vasodilator, and later as a calcium channel antagonist, but recent data suggests that it acts as a cardiac metabolic agent, through inhibition of the enzyme, carnitine palmitoyltransferase-1 (CPT-1). Given the drug's unique anti-ischemic action and favorable hemodynamic profile, together with an improved understanding of the mechanisms underlying the adverse effects of the drug and the clear clinical need for additional therapies in refractory patients, perhexiline is currently being re-appraised as a potentially useful agent in the management of severe myocardial ischemia. Perhexiline is being considered for registration or re-registration in a number of countries and is being evaluated in a large-scale clinical trial in elderly patients with aortic stenosis and myocardial ischemia. This systematic review examines the evidence from available published literature in relation to the efficacy and tolerability of perhexiline in the treatment of cardiac disease. While there is a lack of well designed controlled trials using objective end-points to determine efficacy (almost all trials used a crossover design, included small numbers of patients and had limited statistical analysis of results), there is consistency in the data available that perhexiline is considerably more effective than placebo when used as monotherapy. Furthermore, it affords additional symptom relief in those already receiving maximal conventional anti-anginal therapy. However, there is a paucity of trials demonstrating the efficacy of low dosages of perhexiline (100 to 200 mg/day) in patients with refractory angina pectoris. Available evidence also suggests that the incidence of adverse events can be minimised, and the efficacy maintained, by keeping plasma perhexiline concentrations within a therapeutic range (150 to 600 micro g/L)

Assessment of interlaboratory performance in the provision of perhexiline therapeutic drug monitoring services in Australia.

Perhexiline is a prophylactic antianginal agent particularly useful in patients whose angina is poorly controlled or refractory to conventional drug regimens. Although perhexiline can cause serious hepatic and neurological toxicity, maintaining trough plasma concentrations between 0.15-0.60 mg/L minimizes the risk of toxicity while providing relief of angina symptoms in a majority of patients. All pathology laboratories are required to participate in interlaboratory proficiency testing (PT) programs. The authors therefore initiated a monthly PT program to assess the performance of Australian laboratories measuring perhexiline (n = 8). PT specimens included perhexiline-spiked drug-free human plasma and pooled plasma from patients administered perhexiline. The performance of 8 Australian laboratories participating in the program was examined over a 30-month period. The mean relative standard deviation of the group was 18.2%. All centers performed well with respect to accuracy, achieving mean percentage bias within +/-8% of target perhexiline concentrations. The usefulness of the PT program was highlighted by the identification of two laboratories with an unacceptable degree of variability (up to 30% of results varied more than +/-55% from the target concentration), and the identification of potential analytical problems with the use of perhexiline metabolite concentrations for determining patients' hydroxylator status. Continued and improved use of PT by pathology laboratories is essential to ensuring the safe and effective clinical use of perhexiline.

Perhexiline‐Paroxetine Drug Interaction

Objective: To document a case of perhexiline toxicity associated with concurrent treatment with paroxetine.Clinical Features: An 86‐year‐old woman was admitted to hospital when she was unable to cope at home and because of ataxia, falls, lethargy and nausea. She had started on paroxetine 20 mg daily five weeks before presentation. Investigations revealed elevations in both liver function and serum perhexiline concentration (2.02 mg/L, range 0.15‐0.6 mg/L).Conclusion: Perhexiline toxicity may occur as a result of concurrent treatment with a selective serotonin reuptake inhibitor.

Perhexiline improves symptomatic status in elderly patients with severe aortic stenosis.

The prognosis of severe symptomatic aortic stenosis is poor without aortic valve replacement, with no previous reports of beneficial effects of any medical treatment on either symptoms or outcome. However, this condition is increasingly a disease of the elderly and cardiothoracic surgery is associated with significant mortality and morbidity in this group. We postulated that perhexiline, a novel anti-ischaemic agent with an oxygen-sparing metabolic effect in the myocardium (via inhibition of carnitine palmitoyltransferase-1) and no adverse haemodynamic effects, may improve symptomatic status in elderly patients with severe aortic stenosis. We report here our initial experience with perhexiline treatment in such patients. Elderly patients with symptomatic severe aortic stenosis, who were deemed unsuitable for aortic valve replacement, were treated with perhexiline, the drug dosage titrated according to steady state plasma perhexiline concentrations. NYHA functional class was determined prior to and three months following commencement of perhexiline, and changes were analysed using McNemar's test. Fifteen patients, age range 73-87, were followed for up to 30 months (median 18 months). Symptomatic status improved in 13 of the 15 patients over the first three months of perhexiline therapy (p < 0.01), five patients becoming asymptomatic. Twelve month actuarial survival was 80% (95% CI = 57, 100). Perhexiline was well tolerated, with no withdrawals due to toxicity or deteriorating clinical status. Therapy with perhexiline was associated with a marked improvement in clinical status in this group of elderly patients with severe aortic stenosis.

Application of an Improved HPLC Perhexiline Assay to Human Plasma Specimens

Abstract The analysis of perhexiline in plasma offers an important contribution to the management of patients prescribed such therapy for refractory angina pectoris. Perhexiline has properties and complexities of non-linear kinetics and is subject to genetically predetermined metabolic variants in hydroxylation. The present communication describes a refinement of a previous high performance liquid chromatographic fluorescence method and the application of this method in the therapeutic monitoring of 100 patients at steady-state. The method described is sensitive, accurate and precise, with intra-assay CV's of 2. 1%, 1.4% and 3.7% at concentrations of 150, 750 and 1500 μg/L, and between-assav CV's of 5.7%, 4.7% and 5.8% at 50, 1000 and 3000 μg/L, respectively. The review of patient specimens received in our therapeutic drug monitoring laboratory, suggested that approximately 6% appear to belong to the “poor-hydroxvlation” metabolic sub-population, with a further 16% attaining steady-state plasma perhexiline concentrations above the “therapeutic range” of 150 to 600 μg/L following standard dosage schedules of 100 to 200 mg/day.

Perhexiline maleate treatment for severe angina pectoris — correlations with pharmacokinetics

Perhexiline maleate, which causes inhibition of myocardial fatty acid catabolism with a concomitant increase in glucose utilization, is particularly useful in the management of patients with severe angina pectoris. While perhexiline exerts no significant negative inotropic or dromotropic effects, its short- and long-term use has hitherto been restricted because of complex pharmacokinetics and the eventual development, in many patients, of hepatitis and peripheral neuropathy. Correlations between perhexiline dose, plasma drug concentrations, efficacy and development of toxicity were examined prospectively in 3 groups of patients. The first group ( n = 29) were patients in whom perhexiline was added to previously prescribed anti-anginal medication for short-term (pre-surgical or post-myocardial infarction) control of angina pectoris. Over a mean treatment period of 18 ± 2 (SEM) days, 13 patients experienced a marked reduction in frequency and severity of attacks. No adverse effects occurred. A second group of patients ( n = 19) were treated chronically with 50–400 mg/day of perhexiline, dosage being adjusted to minimize symptoms. Over a mean treatment period of 8.8 ± 1.7 months, 5 patients became asymptomatic, while 9 developed evidence of hepatitis or neurotoxicity, with concomitant plasma perhexiline concentrations of 720–2680 ng/ml. Subsequently, a further group of similar patients ( n = 22) were treated for 12.4 ± 2.6 months, perhexiline dosage being adjusted to maintain plasma perhexiline concentrations below 600 ng/ml. Nine patients became asymptomatic, while none developed adverse effects. It is concluded that perhexiline is useful both as a short-term adjunct to anti-anginal therapy and in the long-term management of patients unsuitable for coronary artery bypass grafting. The risk of long-term toxicity can be reduced markedly by maintenance of plasma drug concentrations below 600 ng/ml without significantly compromising anti-anginal efficacy.

Therapeutic monitoring of the anti-anginal drug perhexiline maleate.

Patients taking oral doses of perhexiline maleate have been examined. Measurement of serum perhexiline concentrations established that different dose requirements between patients were necessary due to the different doses at which drug saturation was achieved. Measurement of serum perhexiline concentrations are essential if side-effects from the drug are to be avoided.

Perhexiline directly inhibits arterial myosin phosphorylation and stimulates cardiac myofibrillar atpase activity

Perhexiline maleate, which causes inhibition of myocardial fatty acid catabolism with a concomitant increase in glucose utilization, is particularly useful in the management of patients with severe angina pectoris. While perhexiline exerts no significant negative inotropic or dromotropic effects, its short- and long-term use has hitherto been restricted because of complex pharmacokinetics and the eventual development, in many patients, of hepatitis and peripheral neuropathy.Correlations between perhexiline dose, plasma drug concentrations, efficacy and development of toxicity were examined prospectively in 3 groups of patients. The first group (n = 29) were patients in whom perhexiline was added to previously prescribed anti-anginal medication for short-term (pre-surgical or post-myocardial infarction) control of angina pectoris. Over a mean treatment period of 18 ± 2 (SEM) days, 13 patients experienced a marked reduction in frequency and severity of attacks. No adverse effects occurred. A second group of patients (n = 19) were treated chronically with 50–400 mg/day of perhexiline, dosage being adjusted to minimize symptoms. Over a mean treatment period of 8.8 ± 1.7 months, 5 patients became asymptomatic, while 9 developed evidence of hepatitis or neurotoxicity, with concomitant plasma perhexiline concentrations of 720–2680 ng/ml. Subsequently, a further group of similar patients (n = 22) were treated for 12.4 ± 2.6 months, perhexiline dosage being adjusted to maintain plasma perhexiline concentrations below 600 ng/ml. Nine patients became asymptomatic, while none developed adverse effects.It is concluded that perhexiline is useful both as a short-term adjunct to anti-anginal therapy and in the long-term management of patients unsuitable for coronary artery bypass grafting. The risk of long-term toxicity can be reduced markedly by maintenance of plasma drug concentrations below 600 ng/ml without significantly compromising anti-anginal efficacy.

High-Performance Liquid Chromatographic Assay of Perhexiline Maleate in Plasma

A sensitive assay is described for the calcium antagonist perhexiline maleate. Alkalinized plasma was extracted with n-hexane, the organic phase was evaporated, and the residue was dansylated prior to analysis by reversed-phase high-performance liquid chromatography using a fluorescence detector. Perhexiline was resolved from its mono- and dihydroxylated metabolites, and the limit of sensitivity was 5ng of perhexiline/ml. This limit represents approximately 100 times the sensitivity of the previously described GLC assay. Single-dose pharmacokinetic studies were performed with 150- and 300-mg oral doses of perhexiline maleate in five patients with severe angina pectoris and impaired left ventricular function. Peak plasma perhexiline levels occurred 3-6hr after drug ingestion in four patients and after 12-18hr in the fifth patient. The mean elimination half-life, measured 24hr after drug ingestion, varied with plasma perhexiline concentration. It was 11.2 ± 2.1hr after the 150-mg dose and 19.1 ± 2.8hr after the 300-mg dose. The mean ratio of areas under the concentration-time curve for the 300- versus 150-mg doses was 5.3:1, suggesting that hepatic metabolism of perhexiline may be saturable and that the bioavailability of perhexiline is dose dependent.