Impaired oxidation of debrisoquine in patients with perhexiline neuropathy.

Abstract

The use of perhexiline maleate as an antianginal agent is occasionally associated with side effects, particularly neuropathy and liver damage. The reason why some individuals develop these toxic reactions is not clear, though some evidence suggests that they may result from impaired oxidative metabolism, due to genetic or hepatic factors, and consequential accumulation of the drug in toxic concentrations. Drug oxidation was measured with an oxidation phenotyping procedure in 34 patients treated with perhexiline, 20 of whom had developed neuropathy and 14 of whom had not. Most of the 20 patients with neuropathy, but not the unaffected patients, showed an impaired ability to effect metabolic drug oxidation. This impairment was independent of hepatic function, concurrent drug therapy, or tobacco or alcohol consumption.The fact that the ability to oxidise several drugs is genetically controlled points to a genetic susceptibility to developing neuropathy in response to perhexiline.

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).…”

Debrisoquine oxidation in an Australian population.

“…The advantage of these modifications is that phenotyping can be offered on a same-day basis. This would be of considerable value when used in a clinical context such as the need to prescribe perhexiline, a drug known to be metabolised by debrisoquine pathway and having significant neurological and hepatic toxicity -0.7 (Shah et al, 1982). The fact that debrisoquine is highly water soluble and is excreted unchanged by the kidneys as well as undergoing extensive first pass metabolism in EM subjects, makes it an ideal drug for population surveys.…”

Extensive oxidative metabolism of dextromethorphan in patients with almitrine neuropathy.

“…In addition to debrisoquine, this isoenzyme is responsible for the genetic polymorphic oxidation of 30 other drugs, including dextromethorphan and perhexiline maleate (Eichelbaum, 1982;Larrey, 1986 (Eichelbaum, 1982;Larrey, 1986). There is a clear association between impairment of debrisoquine oxidation and susceptibility to perhexiline neuropathy (Shah et al, 1982).…”