Impaired oxidation of debrisoquine in patients with perhexiline liver injury.

Abstract

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.

Differences in hepatic drug accumulation and enzyme induction after chronic amiodarone feeding of two rat strains: role of the hydroxylator phenotype?

“…It has been shown that perhexiline-induced liver disease and neuropathy are more frequent in poor hydroxylators when tested with debrisoquine or sparteine (Shah et al, 1982;Morgan et al, 1984). This observation is paralleled by an increased phospholipid accumulation in nervous tissue of rats with a similar genetic hydroxylation defect (Meier et al, 1986).…”

“…However, the fact that drug accumulation and metabolism are so different in the two rat strains studied, points to a possible influence of pharmacogenetic factors on the susceptibility to amiodarone side effects in man. This has been demonstrated for drugs such as perhexiline (Shah et al, 1982;Morgan et al, 1984;Meier et al, 1986).…”

Metabolic Modulation With Perhexiline in Chronic Heart Failure

“…In the absence of dosage adjustment, prolonged, elevated levels lead to phospholipid accumulation, 42 which may also occur with other CPT inhibitors, such as amiodarone. 41 The risk of developing hepatoneurotoxicity with perhexiline is markedly reduced by monitoring and maintaining serum levels between 0.15 and 0.6 mg/L. 26 None of our patients developed abnormal liver function test results or neuropathy as a consequence of perhexiline treatment followed by close serum-level monitoring and titration.…”

Genetically‐determined interaction between propafenone and low dose quinidine: role of active metabolites in modulating net drug effect.

“…This subset is characterized by poor metabolic activity (PM) of debrisoquine 4-hydroxylase. Patients in this group have been considered at high risk for adverse reactions during treatment with drugs whose disposition is dependent on the debrisoquine 4-hydroxylation phenotype because of decreased clearance and hence accumulation of unmetabolized drug (Lennard et al, 1982;Morgan et al, 1984;Oates et al, 1981;Shah et al, 1982). Some investigators have advocated the therapeutic strategy of avoiding such drugs in PM patients (Idle et al, 1983;Lennard et al, 1983).…”