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.