Perhexiline Maleate-Induced Hepatitis

Paliard, P; Vitrey, D; Fournier, Gislene Fátima da Silva Rocha; Belhadjali, J.; Patricot, L M; Berger, F

doi:10.1159/000198145

Cited by 40 publications

(8 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[27] During long term treatment with perhexiline in the 1970s and 1980s, it became apparent that perhexiline was also associated with infrequent but serious adverse effects. [42][43][44] These included neurological adverse effects, hepatic toxicity, [45,46] renal impairment, [46] severe bodyweight loss [47] and hypoglycemia, [48,49] often occurring together in the same patient. These adverse effects appear to be due to accumulation of perhexiline associated with administration of excessive dosages or impaired drug metabolism.…”

Section: Clinical Trial Datamentioning

confidence: 99%

Systematic Review of the Efficacy and Safety of Perhexiline in the Treatment of Ischemic Heart Disease

Killalea

Krum

2001

American Journal of Cardiovascular Drugs

View full text Add to dashboard Cite

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)

show abstract

Section: Clinical Trial Datamentioning

confidence: 99%

Systematic Review of the Efficacy and Safety of Perhexiline in the Treatment of Ischemic Heart Disease

Killalea

Krum

2001

American Journal of Cardiovascular Drugs

View full text Add to dashboard Cite

show abstract

“…Perhexiline is an effective antianginal drug but can cause severe toxicity, notably hepatotoxicity [1–5] and peripheral neuropathy [6–10]. Its pharmacokinetics are complex as it has a long elimination half‐life of days to weeks [11], the steady‐state plasma concentration to dose ratio varies more than a 100‐fold [12], and the systemic clearance is saturable [13].…”

Section: Introductionmentioning

confidence: 99%

Polymorphic hydroxylation of perhexiline in vitro

Sorensen

Sørensen

Miners

et al. 2003

Brit J Clinical Pharma

View full text Add to dashboard Cite

AimsThe aims of this study were to examine the in vitro enzyme kinetics and CYP isoform selectivity of perhexiline monohydroxylation using human liver microsomes. Methods Conversion of rac-perhexiline to monohydroxyperhexiline by human liver microsomes was assessed using a high-performance liquid chromatography assay with precolumn derivatization to measure the formation rate of the product. Isoform selective inhibitors were used to define the CYP isoform profile of perhexiline monohydroxylation. Results The rate of perhexiline monohydroxylation with microsomes from 20 livers varied 50-fold. The activity in 18 phenotypic perhexiline extensive metabolizer (PEM) livers varied about five-fold. The apparent K m was 3.3 ± 1.5 µ M , the V max was 9.1 ± 3.1 pmol min − 1 mg − 1 microsomal protein and the in vitro intrinsic clearance (V max /K m ) was 2.9 ± 0.5 m l min − 1 mg − 1 microsomal protein in the extensive metabolizer livers. The corresponding values in the poor metabolizer livers were: apparent K m 124 ± 141 µ M ; V max 1.4 ± 0.6 pmol min − 1 mg − 1 microsomal protein; and intrinsic clearance 0.026 µ l min − 1 mg − 1 microsomal protein. Quinidine almost completely inhibited perhexiline monohydroxylation activity, but inhibitors selective for other CYP isoforms had little effect. Conclusions Perhexiline monohydroxylation is almost exclusively catalysed by CYP2D6 with activities being about 100-fold lower in CYP2D6 poor metabolizers than in extensive metabolizers. The in vitro data predict the in vivo saturable metabolism and pharmacogenetics of perhexiline.

show abstract

“…-12 The neuropathy and the hepatic damage may not reverse when the drug is withdrawn and deaths have been recorded. [11][12][13][14][15][16][17][18] Severe adverse reactions follow the use of perhexiline in only a percentage of patients and are perhaps associated with impaired metabolism of the drug. Perhexiline is a lipophilic drug and its elimination depends on hepatic oxidation to the more polar monohydroxylated and dihydroxylated metabolites.19 Several drug oxidations in man are under single gene control and exhibit genetic polymorphism.2t21 Oxidation is regulated by two alleles, DH-rapid and extensive oxidation and DL_ slow impaired oxidation.2' Individuals homozygous for the DL allele have an impaired ability to.oxidise many drugs.…”

mentioning

confidence: 99%

“…"'12 13 18 29 30 The course of the liver patients are biopsied. Poupon et a133 for example, disease is variable; usually transaminase values studied 46 patients on maintenance perhexiline and return to normal within a month of perhexiline found hepatomegaly in 13% (6/46), raised serum withdrawal4 31 although in some patients the liver bile acid values in 57% (26/46) abnormal BSP lesion progresses despite withdrawal of the drug.1' retention in 74% (34/46) but evidence of histological The mortality in patients who develop cirrhosis is damage in all 11 patients in whom liver biopsy was high [11][12][13][14][15][16][17][18]. …”

mentioning

confidence: 99%

Impaired oxidation of debrisoquine in patients with perhexiline liver injury.

Morgan¹,

Reshef²,

Shah³

et al. 1984

Gut

150

View full text Add to dashboard Cite

SUMMARY 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.

show abstract

Perhexiline Maleate-Induced Hepatitis

Cited by 40 publications

References 0 publications

Systematic Review of the Efficacy and Safety of Perhexiline in the Treatment of Ischemic Heart Disease

Systematic Review of the Efficacy and Safety of Perhexiline in the Treatment of Ischemic Heart Disease

Polymorphic hydroxylation of perhexiline in vitro

Impaired oxidation of debrisoquine in patients with perhexiline liver injury.

Contact Info

Product

Resources

About