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.

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

Long term perhexiline maleate therapy causes peripheral neuropathy and hepatic damage in certain subjects. An association between these adverse reactions and a genetically determined relative inability to hydroxylate debrisoquine has been described. This association could indicate either that the effects of perhexiline impair debrisoquine oxidation thus producing a phenocopy, or that perhexiline is polymorphically hydroxylated and that the polymorphism is controlled by the same alleles as control the debrisoquine polymorphism. To test the second possibility, a study investigating the hydroxylation status of a population of healthy volunteer subjects has been performed using perhexiline maleate. Hydroxylation phenotyping was performed on 50 normal volunteers. A standard oral dose was given and plasma and urinary perhexiline, 4-monohydroxyperhexiline (MI metabolite), and 4'monohydroxyperhexiline (MIII metabolite) was measured. The 24-hour plasma perhexiline concentration, the 24-hour plasma MI metabolite concentration, and 12 to 24-hour urinary MI metabolite excretion were clearly bimodal, suggesting the existence of a polymorphism for perhexiline hydroxylation. Poor metabolisers represent 6% of the population studied. Known poor metabolisers of debrisoquine are also poor metabolisers of perhexiline, while known extensive metabolisers of debrisoquine are also extensive metabolisers of perhexiline, indicating that in white British subjects the hydroxylation polymorphism is under identical genetic control for both compounds. The poor metaboliser sub-group exhibited the highest plasma perhexiline levels. Perhexiline phenotyping separates the poor and extensive metaboliser phenotypes much more clearly than other tests and defines a sub-group at risk from perhexiline toxicity. Pretreatment phenotyping using this test, followed by exclusion of poor metabolisers from perhexiline therapy, should substantially reduce the incidence of major adverse effects.

https://jmg.bmj.com/content/jmedgenet/21/1/27.full.pdf

Polymorphic hydroxylation of perhexiline maleate in man.

Peripheral neuropathy has been noted as a complication of therapy with perhexiline maleate, a drug widely used in France (and in clinical trials in the United States) for the prophylactic treatment of angina pectoris. In 24 patients with this complication, the marked slowing of motor nerve conduction velocity and the electromyographic changes imply mainly a demyelinating disorder. Improvement was noted with cessation of therapy. In a few cases the presence of active denervation signified a poor prognosis, with only slight improvement. The underlying mechanism causing the neuropathy is not yet fully known, although some evidence indicates that it may be a lipid storage process.

Perhexiline maleate and peripheral neuropathy

Drug-induced experimental lipidosis in the nervous system.

Perhexiline maleate reduced the growth of human skin fibroblasts in cell culture at a concentration range of 0.3-3 micrograms/ml. At the highest concentration, the cells survived only four days. Pleomorphic inclusions characteristic of drug-induced phospholipidoses appeared in cultured cells. Analysis of the major lipid classes was performed on cells exposed to 3 micrograms/ml at four days. Gangliosides, phospholipids and cholesterol levels four to six times above controls were found. No major qualitative abnormalities were detected in phospholipids. On the contrary, an abnormal pattern of gangliosides was seen by densitometry of silica gel thin-layer plates with increases of GD3 and of an unknown ganglioside. Drug induced lipidosis may involve other lipids than phospholipids, particularly gangliosides.

Perhexiline maleate-induced lipidosis in cultured human fibroblasts: cell kinetics, ultrastructural and biochemical studies.

Neuropathies périphériques au maléate de perhexiline.

[Peripheral neuropathies due to perhexiline maleate (author's transl)].

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Neuropathies périphériques au maléate de perhexiline.

[Peripheral neuropathies due to perhexiline maleate (author's transl)].