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

Singlas, E; Goujet, M. A.; Simon, Peter F. W.

doi:10.1007/bf02089960

Cited by 85 publications

(48 citation statements)

References 3 publications

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“…The polymorphic enzyme system is stereoselective, as demonstrated by there being a bigger difference between phenotypes in M 1 production than in M 3 production, thus confirming the results of previous studies [5,6]. Secondly, we have confirmed the previously noted very slow elimination of perhexiline and its metabolites, even in EM [6,7,10,11]. Thirdly, we have found a biphasic urinary elimination of M 1 and M 3 in intact extensive oxidizers, whereas only the first phase of this elimination was seen in subjects with T-tube drainage.…”

Section: Discussionsupporting

confidence: 91%

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Studies on the metabolism of perhexiline in man

Cooper

Evans

Price

1987

Eur J Clin Pharmacol

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We have studied the disposition of perhexiline and its two major metabolites, M1 and M3, in healthy volunteers and in patients with biliary T-tube drains after cholecystectomy. In healthy volunteers the genetic control for impaired hepatic oxidation is identical for debrisoquine, sparteine, and perhexiline. Poor metabolizers demonstrate markedly reduced production and excretion of the major metabolite, M1. Their production of M3 is also reduced, but to a lesser degree than for M1, confirming substrate stereoselectivity by hepatic oxidases. Biphasic urinary elimination of M1 and M3 is seen in intact extensive oxidizers, whereas only the first phase is apparent in patients with biliary T-tube drainage. This suggests the possibility of enterohepatic recycling of these compounds, which may account for their prolonged elimination. More than 90% of an ingested dose of perhexiline maleate remains unaccounted for at 24 h after ingestion, even in extensive metabolizers. A careful, radiolabelled tissue-distribution study is warranted to elucidate the complicated metabolic fate of perhexiline.

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Section: Discussionsupporting

confidence: 91%

“…Prolonged plasma and urinary elimination times are observed for perhexiline, M1, and M3, with half-times ranging from 2 to 15 days in most studies [6,7,10,11], the elimination times being longest in PM [6,7]. The mechanisms responsible for this prolonged elimination are not known.…”

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confidence: 95%

Studies on the metabolism of perhexiline in man

Cooper

Evans

Price

1987

Eur J Clin Pharmacol

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“…4,4'-DH can be found in tissue 18 months after the drug is discontinued, whereas the half-life of perhexiline in patients with neuropathy ranges between 9 and 22 days. 39 Similar morphologic changes to those described with amiodarone and other drugs occur during the de- …”

Section: Methodssupporting

confidence: 55%

Amiodarone and its desethyl metabolite: tissue distribution and morphologic changes during long-term therapy.

Adams¹,

Holt²,

Storey³

et al. 1985

Circulation

157

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The pharmacokinetic characteristics of amiodarone suggest extensive tissue deposition. We confirmed this by measuring tissue concentrations of the drug and of its major metabolite, desethylamiodarone, in human tissues. These were obtained at autopsy (n = 9), surgery (n = 7), or biopsy (n = 2) from 18 patients who had been treated with amiodarone for varying periods of time. (89 and 470). and lymph node (83 and 316). We also found high concentrations of amiodarone (306 mg/kg wet weight) and desethylamiodarone (943 mg/kg wet weight) in abnormally pigmented ("blue") skin from patients with amiodarone-induced skin pigmentation. These values were 10-fold higher than those in unpigmented skin from the same patients. These high concentrations were associated with lysosomal inclusion bodies in dermal macrophages in the pigmented skin. The inclusion bodies were intrinsically electron dense and were shown to contain iodine by energy dispersive xray microanalysis. Lysosomal inclusion bodies shown by electron microscopy to be multilamellar were seen in other tissues. These tissues included terminal nerve fibers in pigmented skin, pulmonary macrophages. blood neutrophils. and hepatocytes and Kupffer cells. These characteristic ultrastructural findings occur in both genetic lipidoses and lipidoses induced by other drugs, e.g., perhexiline. We conclude that during therapy with aniodarone, widespread deposition of amiodarone and desethylamiodarone occurs. This leads to ultrastructural changes typical of a lipidosis. These changes are seen clearly in tissues associated with the unwanted effects of amiodarone, e.g., skin, liver and lung. Circulation 72, No. 5, 1064-1075, 1985 AMIODARONE is recognized as an orally effective agent in the treatment of atrial and ventricular arrhythmias refractory to conventional therapy. It is a benzofuran derivative containing two iodine atoms per molecule. In man, only one major metabolite has been identified, desethylamiodarone.' During long-term therapy this compound reaches similar plasma concentrations to amiodarone, and both compounds show long terminal elimination half-lives reflecting a com-

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“…However, it emerged that this toxicity reflected drug accumulation in plasma [7] which in turn resulted from inter-individual variability in CYP2D6-mediated metabolism [8,9]. With widespread availability of therapeutic drug monitoring [10,11] and greater understanding of its potential widespread utility for disorders of cardiac energetics [12], the clinical use of perhexiline is now increasing.…”

Section: Introductionmentioning

confidence: 99%

“…It is highly protein bound and has a large volume of distribution. As it is subject to hepatic metabolism by CYP2D6, the plasma half-life of perhexiline ranges from several hours to several weeks [7,13].…”

Section: Introductionmentioning

confidence: 99%

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

Chong

Drury

Licari

et al. 2015

Eur J Clin Pharmacol

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Metabolism PharmacokineticsDrug uptake Stereoselectivity 3 ABSTRACT (150-250 words)Purpose: Perhexiline is a prophylactic anti-ischaemic agent with weak calcium antagonist effect which has been increasingly utilized in the management of refractory angina. The metabolic clearance of perhexiline is modulated by CYP2D6 metaboliser status and stereoselectivity. The current study sought to determine (1) whether the acute accumulation of perhexiline in the myocardium is stereoselective, and (2) to 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 atria, and there was more rapid clearance of (-) .005]. Atrial uptake of (+)-enantiomer also varied directly with duration of therapy (r=0.29, p=0.004), while atrial uptake of (-)-perhexiline varied inversely with simultaneous heart rate (r=-0.22, p=0.03). 4Conclusion: (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.(Word count: 235 words) 5

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

Cited by 85 publications

References 3 publications

Studies on the metabolism of perhexiline in man

Studies on the metabolism of perhexiline in man

Amiodarone and its desethyl metabolite: tissue distribution and morphologic changes during long-term therapy.

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

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