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PubMed1999

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.

Angina Pectoris↗
PubMed2003

Correlation of CYP2D6 genotype with perhexiline phenotypic metabolizer status.

Perhexiline is metabolized by CYP2D6 and has concentration-related hepatoxicity and peripheral neuropathy. The risk of toxicity is reduced using therapeutic drug monitoring. CYP2D6 genotyping before therapy may allow earlier appropriate dosing. This study aimed to determine whether assessment of CYP2D6 genotype in patients on perhexiline could predict accurately metabolizer status as determined by the perhexiline metabolic ratio (MR). Blood samples from patients stabilized on perhexiline were analysed for CYP2D6 genotype and for concentrations of perhexiline and its hydroxy metabolite. The MR was determined. Of 74 patients, five were poor metabolizers (PM) defined by a MR<0.4, and the remainder were extensive metabolizers (EM). The genotypes were: *1/*1 (n=21), *1/*4 (n=18), *1/*2 (n=12), *1/*3 (n=2), *1/*5 (n=1), *1/*9 (n=2), *1/*10 (n=2), *2/*4 (n=4), *2/*2 (n=3), *4/*41 (n=3), *2/*41 (n=1), *41/*41 (n=1), *4/*9 (n=1), *4/*5 (n=1), *5/*6 (n=1) and *4/*6 (n=1). Allele frequencies were consistent with those reported in population studies. The 3 PMs with the lowest MR were predicted by genotype (*4/*5, *5/*6, *4/*6). The other 2 PMs had intermediate metabolizer genotypes and were on CYP2D6 inhibiting drugs. Amongst the EMs, the highest MR was associated with *1 and *2 allele combinations and the MR was progressively lower with the presence of alleles with intermediate function (*9, *10, *41) followed by alleles with no functional product (*3, *4, *5, *6). Thus, a gene-dose effect was observed. Genotype predicted PM phenotype and also intermediate metabolizers. Determination of CYP2D6 genotype before therapy with perhexiline may help predict perhexiline dose requirements and reduce the risk of perhexiline concentration-related toxicity.

Adult↗
PubMed2005

Dissociation between metabolic and efficiency effects of perhexiline in normoxic rat myocardium.

The antianginal agent perhexiline inhibits rat cardiac carnitine palmitoyltransferase-1 (CPT-1) and CPT-2, key enzymes for mitochondrial transport of long-chain fatty acids. We tested the hypothesis that perhexiline, in therapeutic concentrations (2 microM), inhibits palmitate oxidation and enhances glucose oxidation in isolated rat cardiomyocytes and in the working rat heart, thereby increasing efficiency of oxygen utilization. In isolated cardiomyocytes, perhexiline (2 microM) exerted no acute effects on palmitate oxidation, but after 48 hours pre-exposure oxidation was inhibited by perhexiline (2 to 10 microM) by 15% to 35% (P < 0.0002). In non-ischemic working rat hearts (3%BSA, 0.4 mM palmitate, 11 mM glucose, 100 microU/mL insulin) perhexiline (2 microM) had no significant acute effect on cardiac efficiency, palmitate or glucose oxidation, but 24 hours pretreatment with transdermal perhexiline increased cardiac work (by 29%, P < 0.05) and cardiac efficiency (by 30%, P < 0.02) without significant effects on palmitate oxidation. The selective CPT-1 inhibitor oxfenicine (2 mM) inhibited palmitate oxidation and enhanced glucose oxidation, but failed to enhance cardiac efficiency. In conclusion, in the non-ischemic working rat heart, perhexiline increases myocardial efficiency by a mechanism(s) that is largely or entirely independent of its effects on CPT. Effects on cardiac efficiency during ischemia, and with changes in fatty acid oxidation after longer perhexiline pretreatment remain to be determined.

Animals↗
PubMed1997

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

BACKGROUND: 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. AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Therapy with perhexiline was associated with a marked improvement in clinical status in this group of elderly patients with severe aortic stenosis.

Aged↗
PubMed1984

Impaired oxidation of debrisoquine in patients with perhexiline liver injury.

Perhexiline maleate is an antianginal agent which depends on hepatic oxidation for its elimination. Its use may be complicated by the development of peripheral neuropathy and liver damage. The majority of patients with perhexiline neuropathy have an impaired ability to effect metabolic drug oxidation which is genetically determined. Information has not been available on drug oxidation capacity in patients with perhexiline liver injury. Drug oxidation was measured using an oxidation phenotyping procedure in four patients with perhexiline liver injury and in 70 patients with chronic liver disease serving as a control group. All four patients with perhexiline liver damage showed a substantial metabolic defect; three of the four patients (75%) showed a genetically determined impairment of oxidation capacity. The incidence of severely impaired oxidation capacity in the perhexiline group was significantly greater than in the patients with chronic liver disease (6/70; 8.6%) and in the healthy population (9%) (F = 0.0048). A clear association exists between perhexiline liver injury and diminished drug metabolic activity, suggesting that the propensity to develop perhexiline liver injury is, at least in part, genetically determined.

Adolescent↗
PubMed2001

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)

Angina Pectoris↗
PubMed1995

Voltage- and time-dependent block by perhexiline of K+ currents in human atrium and in cells expressing a Kv1.5-type cloned channel.

Perhexiline maleate is an antianginal drug that has been shown to have antiarrhythmic effects in humans. To examine whether some of these clinical observations could be caused by block of cardiac K+ channels, we examined the effects of perhexiline on a rapidly activating delayed rectifier K+ channel (Kv1.5) cloned from human heart and stably expressed in human embryonic kidney cells as well as a corresponding K+ current (the ultra-rapid delayed rectifier, IKur) in human atrial myocytes. With the use of inside-out macropatches, we found that perhexiline inhibited Kv1.5 current in a time- and voltage-dependent manner with an IC50 value of 1.5 x 10(-6) M at +50 mV. Perhexiline reduced Kv1.5 tail current amplitude and slowed its decay relative to control. These data are consistent with blockade of open channels, probably from the intracellular surface. Perhexiline (3 microM) also blocked IKur in human atrial myocytes. The block that was observed was both time- and voltage-dependent in qualitatively similar ways to block of Kv1.5 channels. However, the time-dependent block of IKur by perhexiline was somewhat slower and its voltage-dependence steeper relative to its effects on Kv1.5. These data indicate that perhexiline blocks both cloned and native human cardiac K+ channels. Blockade of one or more types of voltage-dependent K+ channels may explain some of the electrophysiological effects of perhexiline observed in humans.

Atrial Function↗
PubMed1981

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 nb-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 5 ng 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 3-6 hr after drug ingestion in four patients and after 12-18 hr in the fifth patient. The mean elimination half-life, measured 24 hr after drug ingestion, varied with plasma perhexiline concentration. It was 11.2 +/- 2.1 hr after the 150-mg dose and 19.1 +/- 2.8 hr after the 300-mg dose. The mean ratio of areas under the concentration-time curve for the 300-versus 150-mg doses ws 5.3:1, suggesting that hepatic metabolism of perhexiline may be saturable and that the bioavailability of perhexiline is dose dependent.

Aged↗
PubMed1999

The effects of perhexiline on the rat coronary vasculature.

The predominant site and mechanism(s) of perhexiline-induced coronary vasodilatation were investigated in the rat heart. Perhexiline was more potent in the Langendorff perfused heart than in the left anterior descending coronary artery (EC50; 0.27 microM, confidence limits 0.19-0.39: 2.7 microM, 2.0-3.4, respectively). Selective endothelial inactivation with Triton X-100 in the perfused heart, reduced the response to perhexiline 1 microM (76+8% to 30+3% of control). 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) 3 microM, Nomega-nitro-L-arginine 100 microM, or a combination of the latter with indomethacin 10 microM, had no significant effect on responses to perhexiline in the perfused heart. Unlike bradykinin-induced vasodilatation, responses to perhexiline were not inhibited by tetrabutylammonium 1 mM, or charybdotoxin 20 nM. SKF525A 5 microM inhibited both perhexiline and bradykinin responses, while apamin 1 microM and glibenclamide 3 microM inhibited neither. Perhexiline exerts partially endothelium-dependent coronary vasodilator effects in the rat, predominantly on small coronary arteries, which appear to be independent of nitric oxide (NO), prostacyclin and the endothelium-derived hyperpolarising factor (EDHF) released by bradykinin.

Animals↗
PubMed1984

Single-dose pharmacokinetics of perhexiline administered orally to humans.

A high-performance liquid chromatographic method for the simultaneous determination of perhexiline and its major metabolites, the cis- and trans-monohydroxyperhexilines M1 and M3, respectively, in human plasma or urine has been developed. Perhexiline and its metabolites are extracted from plasma or urine and derivatized with 1-fluoro-2,4-dinitrobenzene. The extracted dinitrophenyl derivatives of drug and metabolites are separated on a Spherisorb S5 ODS column by gradient elution. The limits of detection for perhexiline and its monohydroxy metabolites were 15 and 3 ng/ml, respectively. The inter-assay coefficients of variation for 100 ng/ml perhexiline, 100 ng/ml M1 and 400 ng/ml M3 were 10.5, 7.6 and 5.6%, respectively (n = 9). The method has been employed in a limited kinetic study with five healthy adult male volunteers who received 150-mg and 300-mg Pexid tablets at an interval of one week. In four subjects perhexiline exhibited marked first pass effects, with plasma M1 levels higher than unchanged perhexiline; in the urine M1 was the predominant metabolite except in one subject who had higher M3 than M1 in the 300-mg Pexid study. The fifth subject exhibited a defective capacity to hydroxylate perhexiline; M1 and M3 were not detectable in plasma, and the urinary excretion of the monohydroxyperhexilines was relatively less, with M3 present in higher amounts than M1.

Administration, Oral↗
PubMedDate not supplied

Vasodilating effects of perhexiline, glyceryl trinitrate, and verapamil on the coronary, femoral, renal, and mesenteric vasculature of the dog.

We compared the vasodilator effects of perhexiline on canine coronary, femoral, renal, and mesenteric arteries with those of glyceryl trinitrate and verapamil. Intravenous perhexiline produced vasodilation of all four vascular beds and decreased peripheral vascular resistance. High doses of perhexiline sometimes increased peripheral vascular resistance and reduced peripheral blood flow. This increase in resistance was abolished by hexamethonium. Intra-arterial perhexiline caused dose-dependent dilation in all four vascular beds without selectivity for the coronary circulation. Neither the autonomic nervous system nor inhibition of adenosine deaminase was involved in the vasodilator action of perhexiline. Perhexiline abolished renal blood flow autoregulation, an effect which was reversed by simultaneous administration of CaCl2. These results suggest that the vasodilator effect of perhexiline is mediated by its Ca2+-antagonistic activity. However, some differences in its effects from those of other Ca2+-antagonists remain to be clarified.

Animals↗
PubMedDate not supplied

Effect of perhexiline on atrioventricular nodal function of anesthetized dogs.

We investigated the effects of perhexiline, a calcium-antagonistic vasodilator, on atrioventricular (AV) conduction in anesthetized open-chest dogs and in isolated, blood-perfused AV node preparations of the dog. Perhexiline, 3 mg/kg, prolonged the AV conduction time from 103.0 +/- 4.4 to 115.3 +/- 4.0 msec (p less than 0.05) in dogs with intact cardiac nerves. In dogs on which vagotomy and stellectomy had been performed, basal AV conduction time was 119.0 +/- 5.0 msec; 3 mg/kg of perhexiline barely prolonged it (121.0 +/- 7.0 msec). Thus, the negative dromotropic effect of perhexiline was abolished by denervation. The functional refractory period of the AV node was also lengthened with 3 mg/kg of perhexiline in the nerve-intact dogs (from 246.0 +/- 15.7) to 270.0 +/- 15.5 msec), but was scarcely affected by perhexiline in the cardiac denervated dogs (from 296.7 +/- 15.7 to 303.2 +/- 13.6 msec). Verapamil, 0.1-0.3 mg/kg, exerted a negative dromotropic effect in both innervated and denervated hearts. A direct inhibitory effect of perhexiline on AV conduction was observed in isolated blood-perfused AV node preparations, but it was much weaker when compared with that of verapamil.

Animals↗
PubMed1981

Effects of perhexiline on hemodynamics in anesthetized open-chest dogs.

Cardiohemodynamic effects of perhexiline were investigated in anesthetized open-chest dogs, measuring blood flow rates of the pulmonary artery (PAF), superior and inferior venae cavae (SVCF and IVCF), right atrial pressure (RAP), systemic blood pressure (SBP), and heart rate (HR). Sum of SVCF and IVCF was interpreted as venous return (VR). Perhexiline, 0.3-3 mg/Kg, injected intravenously over 2 min caused dose-dependent increases in PAF, VR, and RAP, followed by decreases in PAF and VR at higher doses. SBP and HR were depressed with perhexiline dose-dependently. Verapamil, 0.03-0.3 mg/Kg, also increased PAF, VR, and RAP to the lesser extent than perhexiline. Verapamil decreased these variables except RAP more markedly than perhexiline. Treatment with propranolol (1 mg/Kg) and phentolamine (1 mg/Kg) which completely blocked cardiohemodynamic effect of 1 microgram/Kg of norepinephrine, markedly attenuated the effects of perhexiline on VR and PAF but not completely. It is concluded that the effect of perhexiline to increase VR and PAF is in most part mediated through the cardiovascular reflex control for blood pressure reduction by the drug, though a direct effect on capacitance vessels may be included.

Anesthesia↗
PubMed1997

Interaction of serotonin re-uptake inhibitors with perhexiline.

OBJECTIVE: To report two cases of perhexiline toxicity associated with selective serotonin re-uptake inhibitor (SSRI) treatment. CLINICAL PICTURE: Serum perhexiline concentrations progressively increased after a 69-year-old man was concurrently prescribed paroxetine for the treatment of depression. An 84-year-old woman was admitted to hospital with severe, symptomatic perhexiline toxicity associated with fluoxetine treatment. TREATMENT: In both cases, perhexiline therapy was suspended and treatment with SSRIs was withdrawn. OUTCOME: Serum perhexiline concentrations declined following the withdrawal of paroxetine in one case, but in the case of the second patient perhexiline concentrations were extremely slow to decrease, resulting in referral to a rehabilitative care unit for convalescence. CONCLUSIONS: Serum perhexiline concentrations may be elevated during concurrent treatment with SSRIs, potentially resulting in severe toxicity.

Aged↗
PubMed1985

Effects of the calcium antagonists perhexiline and cinnarizine on vascular and cardiac contractile protein function.

The weakly basic, lipophilic Ca++ antagonists perhexiline and cinnarizine have been compared with the calmodulin inhibitor W-7 and the cardiotonics Vardax and APP-201-533 for the ability to modulate Ca++-dependent contractile protein interactions directly, as well as Ca++-calmodulin-mediated myosin light chain phosphorylation, in arterial actomyosin or cardiac myofibrils. Both perhexiline and cinnarizine inhibited arterial myosin P-light chain phosphorylation and superprecipitation of arterial actomyosin over the concentration range of 10 to 200 microM. Concomitant inhibition of arterial superprecipitation and phosphorylation by perhexiline (IC50 = 33 microM) and cinnarizine (IC50 = 60 microM) was similar to W-7 (IC50 = 35 microM), and was characterized by a rightward shift in the pCa superprecipitation and pCa-light chain phosphorylation relationships, depressed maximum activity and attenuation by 2 microM exogenous calmodulin. However, whereas inhibition of superprecipitation and P-light chain phosphorylation by W-7 was equal at different Mg++ concentrations, relatively greater inhibition with perhexiline and less inhibition with cinnarizine was apparent as the free Mg++ concentration was lowered. In cardiac myofibrils prepared from both bovine and canine ventricles, perhexiline stimulated Mg-adenosine triphosphatase (ATPase) activity and cinnarizine was without effect, whereas W-7 significantly depressed ATPase activity. Perhexiline was 10-fold more potent and 3-fold more efficacious than either Vardax or APP-201-533 in canine cardiac myofibrils. Whereas APP-201-533 increased Ca++ sensitivity and maximum ATPase activity (Vmax), perhexiline increased Ca++ sensitivity, but not Vmax, and W-7 depressed both parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphatases↗
PubMed1984

Reversal of acquired resistance to doxorubicin in P388 murine leukemia cells by perhexiline maleate.

The effects of perhexiline maleate on growth and drug sensitivity were studied in the P388 murine leukemia cell line and in an anthracycline-resistant subline (P388/ADR). At noninhibitory concentrations, perhexiline maleate markedly increased the sensitivity of P388/ADR cells to doxorubicin but did not have such an effect on anthracycline-sensitive cells. The effects of perhexiline maleate on P388/ADR cells were reversible. Perhexiline maleate also increased the accumulation of another anthracycline, daunorubicin, in P388/ADR cells but did not increase its accumulation in the anthracycline-sensitive cells. Perhexiline maleate did not affect the sensitivity of either cell line to methotrexate or to 6-mercaptopurine. However, its effects on the sensitivity and on drug accumulation of vinblastine, a drug to which P388/ADR cells are cross-resistant, were similar to those observed for the anthracyclines. Although perhexiline maleate has been reported to be a calcium antagonist in other systems, our data do not suggest that this mechanism is involved in its enhancement of the sensitivity of P388/ADR cells to doxorubicin. We suggest instead that this effect might be associated with alterations of cell lipid metabolism induced by perhexiline maleate.

Animals↗
PubMed1977

Effects of perhexiline on survival time and infarct size in experimental myocardial infarction.

The effects of perhexiline on survival time and infarct size were studied in three animal models. Dogs pretreated orally with perhexiline, 200 mg/day/14 days, and monitored under anesthesia for 30 hours after ligation of the left anterior descending coronary artery (LAD) had infarct weights of 9.1+/-1.9 g as compared to 15.2+/-1.0 g in paired untreated controls (P less than .02). Twelve of 15 perhexiline-pretreated dogs survived the duration of these studies while only 5 of 15 control animals survived for the same period of time (P less than .05). Serum creatine phosphokinase activity was significantly lower in the treated dogs at 9, 12 and 15 hours after ligation (P less than .05). Conscious dogs, pretreated orally with perhexiline 200 mg/day/7 days or 400 mg/day/7 days and monitored without anesthesia or analgesia for 72 hours after coronary ligation had smaller infarcts (P200=26+/-5; P400=26+/-4; C=39+/-5 g; P less than .05) lower plasma peak creatine phosphokinase activity (P less than .05) and reduced heart rate (P400=198+/-8; C=226+/-8 beats/min; P less than .05) and reduced incidence of ventricular ectopic beats (P less than .05). In pentobarbital anesthetized open-chest dogs, perhexiline (3 mg/kg i.v.) reduced the sum of S-T segment elevation after left anterior descending coronary artery occlusion from 32+/-3 to 14+/-1 mV (P less than .001); this effect was associated with and/or preceded by a reduction in arterial pressure (101+/-4 to 78+/-5 mm Hg; P less than .001) and heart rate (151+/-8 to 138+/-7 beats/min P less than .025; Circumflex flow increased from 38+/-4 to 83+/-8 ml/min (P less than .01). In noninfarcted open-chest dogs, perhexiline administration (3 mg/kg i.v.) resulted in increases in coronary blood flow, narrowing of arterial-coronary sinus O2 difference and a 14% reduction in myocardial O2 consumption. The protective effects of perhexiline on the ischemic myocardium appear to result from reductions in heart rate and associated decrease in myocardial O2 demand as well as an antiarrhythmic effect.

Animals↗
PubMed1978

Pharmacokinetics of perhexiline maleate in anginal patients with and without peripheral neuropathy.

Perhexiline maleate (Pexid) which has been in general use in France with good results for the treatment of angina pectoris since 1973, may be associated with severe side effects including peripheral neuropathy. The present study is a comparison of the pharmacokinetics of perhexiline maleate in anginal patients with and without signs of peripheral neuropathy. Compared to the latter, those with neuropathy had higher plasma levels of perhexiline, slower hepatic metabolism and a longer plasma half-life. Thus, peripheral neuropathy associated with perhexiline maleate treatment appears to be a direct toxic effect due to accumulation of the drug. The accumulation might result either from a decreased volume of distribution secondary to a loss of body weight, possibly drug-induced, or to slow hepatic metabolism of perhexiline of genetic origin or due to hepatic disease, possibly drug-induced. The neuropathy is rarely an isolated event, as it is often associated with one or more adverse effects of perhexiline.

Aged↗