Effect of CYP2D6 metabolizer status on the disposition of the (+) and (−) enantiomers of perhexiline in patients with myocardial ischaemia

Abstract

Perhexiline's pharmacokinetics exhibit significant enantioselectivity in CYP2D6 extensive/intermediate and poor metabolizers, with both enantiomers displaying polymorphic and saturable metabolism via CYP2D6. Clinical use of rac-perhexiline may be improved by developing specific enantiomer target plasma concentration ranges.

CYP2B6, CYP2D6, and CYP3A4 Catalyze the Primary Oxidative Metabolism of Perhexiline Enantiomers by Human Liver Microsomes

“…The microsomal data from this study unequivocally demonstrate that both enantiomers of PHX are subject to significant polymorphic metabolism by CYP2D6, although this enzyme exhibits distinct stereoselectivity with respect to the conformation of metabolites and the rate at which they are formed, consistent with the enantioselective pharmacokinetics observed in vivo for CYP2D6 EMs (Gould et al, 1986;Inglis et al, 2006). This study is the first…”

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

“…This study confirmed that the female DA rat displays perhexiline pharmacokinetics similar to those in humans, with the chosen dosage regimen attaining plasma perhexiline concentrations that approximate the mid to high range of therapeutic concentrations (0.15‐0.60 mg/L). Similar to humans, we report enantioselective plasma pharmacokinetics of perhexiline in female DA rats, consistent with a greater apparent oral clearance of the (−)‐enantiomer. Furthermore, similar to human CYP2D6 extensive / intermediate metabolisers, the dominant metabolite in plasma following administration of the racemate was cis ‐OH‐perhexiline.…”

“…Since the apparent oral clearance of each enantiomer in DA rats was unaffected by the dosage form administered (enantiomer or racemate), and the plasma protein binding of perhexiline is not enantioselective, the steady‐state tissue:plasma concentration ratios should reflect the net tissue uptake of each enantiomer (i.e., the balance between uptake into and elimination from tissue). Therefore, our observations suggest enantioselectivity in the net‐uptake (or tissue binding) of the pure enantiomers, favouring (+)‐perhexiline (2.5‐ to 4.5‐fold greater).…”

“…Perhexiline, a chiral compound, is on the market as a racemic mixture, with no data on the pharmacology of the individual enantiomers, and only pharmacokinetic investigations of the enantiomers, particularly their extensive metabolism by cytochrome P450 2D6 (CYP2D6) . The female Dark Agouti (DA) rat, traditionally an animal model for the human CYP2D6 poor metabolizer phenotype, has previously been utilized to investigate the hepatic and neural toxicity of racemic perhexiline .…”

Pharmacogenetics in cardiology

“…So musste auch der Kalziumantagonist Perhexilin wegen des gehäuften Auftretens von Neuropathien vom Markt genommen werden, Perhexilin ist wie Debrisoquin und Spartein Substrat von CYP2D6, sodass auch in diesem Fall bei Langsammetabolisierern signifikant hö-here Perhexilinplasmakonzentrationen im Vergleich zu schnellen Metabolisierern auftraten [4]. Die Pharmakokinetik von Arzneimitteln wird durch eine Reihe von überwiegend in der Leber exprimierten polymorphen Enzymen beeinflusst.…”