Simultaneous determination of perhexiline and its monohydroxy metabolites in biological fluids by gas chromatography—electron-capture detection

Cooper, Rosemary; Harper, Gregory S.; Price, Allan H.; Evans, David A.; Lockhart, David J.

doi:10.1016/s0378-4347(00)83596-3

Cited by 14 publications

(16 citation statements)

References 10 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%

“…Extracts were derivatized with heptafluorobutyric anhydride and analysed by electron-capture gas chromatography as previously described [7].…”

Section: Analysis Of Samplesmentioning

confidence: 99%

“…Perhexiline oxidation polymorphism has been confirmed [5], poor metabolizers (PM) having raised plasma perhexiline concentrations and prolonged metabolite elimination times when compared with extensive metabolizers (EM) [6,7]. The genetic control of this oxidation is identical to that for debrisoquine and sparteine [5] and phenformin [8].…”

mentioning

confidence: 99%

“…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: 99%

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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%

“…Extracts were derivatized with heptafluorobutyric anhydride and analysed by electron-capture gas chromatography as previously described [7].…”

Section: Analysis Of Samplesmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Studies on the metabolism of perhexiline in man

Cooper

Evans

Price

1987

Eur J Clin Pharmacol

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“…Digoxin is commonly given to adults in a dose of GC with electron capture detection following derivatization also has been used to quantify perhexiline 0.25 mg once daily if renal function is normal. The usually accepted therapeutic plasma concentration range and metabolites in plasma [147]. However, given the very high and stereoselective disposition of the is between 0.5 and 2.0 ng ml There is some clinical trial evidence that efficacy is concentration-dependent value of such nonstereoselective assays, and the likely association between concentration of racemic drug within the therapeutic range, and considerable evidence of concentration-dependence toxicity.…”

Section: Class Ic Drugs (Flecainide Propafenone)mentioning

confidence: 99%

Therapeutic drug monitoring: antiarrhythmic drugs

Campbell

Williams

2001

Brit J Clinical Pharma

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Antiarrhythmic agents are traditionally classified according to Vaughan Williams into four classes of action. Class I antiarrhythmic agents include most of the drugs traditionally thought of as antiarrhythmics, and have as a common action, blockade of the fast-inward sodium channel on myocardium. These agents have a very significant toxicity, and while they are being used less, therapeutic drug monitoring (TDM) does significantly increase the safety with which they can be administered. Class II agents are antisympathetic drugs, particularly the b-adrenoceptor blockers. These are generally safe agents which do not normally require TDM. Class III antiarrhythmic agents include sotalol and amiodarone. TDM can be useful in the case of amiodarone to monitor compliance and toxicity but is generally of little value for sotalol. Class IV antiarrhythmic drugs are the calcium channel blockers verapamil and diltiazem. These are normally monitored by haemodynamic effects, rather than using TDM. Other agents which do not fall neatly into the Vaughan Williams classification include digoxin and perhexiline. TDM is very useful for monitoring the administration (and particularly the safety) of both of these agents.

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High‐Performance Liquid Chromatographic Analysis of Perhexiline as a Fluorescent Derivative

Huang

Lin

Kou

et al. 2010

J Chinese Chemical Soc

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Perhexiline is an effective drug for angina pectoris, but prolong use of the drug may induce toxicity. A simple and sensitive method was developed for monitoring the drug to avoid over medication. The method is based on derivatizing perhexiline with a fluorescent reagent (2-napththoxy) acetyl chloride. The resulting derivative is highly responsive to a fluorimetric detector (l ex = 230 nm, l em = 347 nm). The lower quantitation limit of the method is attainable at 0.3 mM with a detection limit of about 30 nM (S/N = 3 with 10 mL injected). The method was applicable to the analysis of perhexiline in spiked plasma.

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Simultaneous determination of perhexiline and its monohydroxy metabolites in biological fluids by gas chromatography—electron-capture detection

Cited by 14 publications

References 10 publications

Studies on the metabolism of perhexiline in man

Studies on the metabolism of perhexiline in man

Therapeutic drug monitoring: antiarrhythmic drugs

High‐Performance Liquid Chromatographic Analysis of Perhexiline as a Fluorescent Derivative

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