Enantioselectivity in the tissue distribution of perhexiline contributes to different effects on hepatic histology and peripheral neural function in rats

Abstract

Perhexiline, a chiral drug, is a potent antiischemic agent whose clinical utility is limited by hepatic and neural toxicities. It inhibits mitochondrial carnitine palmitoyltransferase‐1, however, excessive inhibition predisposes toward tissue steatosis. This pilot study investigated the distribution of the two enantiomers and their toxicological potential. Dark Agouti rats (n = 4 per group) were administered vehicle or 200 mg/kg daily of racemic, (+)− or (−)‐perhexiline maleate orally for 8 weeks. Plasma biochemical liver function tests and Von Frey assessments of peripheral neural function were performed. Hepatic and neuronal histology, including lipid and glycogen content, was assessed using electron microscopy. Concentrations of the perhexiline enantiomers and metabolites were quantified in plasma, liver and heart. Plasma perhexiline concentrations following administration of racemate, (+)− or (‐)‐enantiomer were within the mid‐upper clinical therapeutic range. There was extensive uptake of both enantiomers into liver and heart, with 2.5‐ to 4.5‐fold greater net uptake of (+)‐ compared to (−)‐perhexiline (P < .05) when administered as pure enantiomers, but not when administered as racemate. There was no biochemical or gross histological evidence of hepatotoxicity. However, livers of animals administered (+)‐perhexiline had higher lipid (P < .01) and lower glycogen (P < .05) content, compared to those administered (−)‐perhexiline. Animals administered racemic perhexiline had reduced peripheral neural function (P < .05) compared to controls or animals administered (−)‐perhexiline. For the same plasma concentrations, differences in tissue distribution may contribute to disparities in the effects of (+)‐ and (−)‐perhexiline on hepatic histology and neural function.

Perhexiline: Old Drug, New Tricks? A Summary of Its Anti-Cancer Effects

“…These IC50 ranges are similar to the recommended maximum therapeutic plasma concentration of perhexiline of around 2 µmol/L [21]. Small animal studies have demonstrated that perhexiline concentrates further within tissues [26]. Thus, there are anti-tumour effects when the plasma concentration is within the therapeutic range.…”

“…Adjunctive use of perhexiline may increase the inhibition of biological target of interest and result in enhanced overall anti-cancer efficacy. The observation in animal studies that perhexiline concentrates within visceral organs [26] and crosses the blood-brain barrier [34] further makes this drug a favourable cancer therapeutic candidate. It may be a particular benefit for tumours in the central nervous system where the blood-brain barrier, by restricting the effective delivery of many cancer drugs, makes treatment of primary brain cancer and central nervous system metastasis challenging [97].…”

The Antianginal Drug Perhexiline Displays Cytotoxicity against Colorectal Cancer Cells In Vitro: A Potential for Drug Repurposing

“…It can be avoided by careful monitoring of perhexiline plasma concentrations and adjusting dosing to keep plasma concentrations below 0.6 mg/L (equivalent to ~2 µM) [ 5 , 19 , 32 , 33 ]. Compared to plasma, in vivo perhexiline tissue concentrations are markedly higher, as demonstrated in the livers and hearts of rats and humans [ 34 , 35 , 36 ]. Tumour clearance studies show that a daily oral regimen of up to 7 mg/kg (~10 µM) perhexiline for 4 weeks was well tolerated in mice and produced significant reduction in tumour sizes for different tumour types [ 12 , 20 , 22 , 37 ].…”