Perhexiline
Encyclopedia
Perhexiline is a prophylactic antianginal agent used primarily in Australia
and New Zealand
. Perhexiline is thought to act by inhibiting mitochondrial carnitine palmitoyltransferase-1. This shifts myocardial metabolism from fatty acid to glucose utilisation which results in increased ATP production for the same O2 consumption and consequently increases myocardial efficiency. Its clinical use has been limited by its narrow therapeutic index
and high inter- and intra-individual pharmacokinetic
variability. It was outlawed in many countries due to its adverse effects on poor metabolisers (PM). The product has been reintroduced for patients who have contraindications, or have not responded to, other treatments for angina.
. The two main metabolites of perhexiline are the cis and trans isomers of hydroxyperhexiline. CYP2D6 accounts for only a small percentage of total hepatic CYP450s but it is one of the main pathways for phase one metabolism of xenobiotic
s. The limited availability of CYP2D6 means perhexiline metabolism is a saturable process.
in the CYP2D6 locus which results in the severely compromised metabolism of at least 25 drugs. It is believed that there are hundreds of potential polymorphism which will result in a PM, some result in functionally deficient CYP2D6, while others cause the absence of CYP2D6.
and peripheral neuropathy
at plasma concentrations >0.6mg/L. The symptoms of peripheral neuropathy include weakness or sensory loss and pain in the arms, hand, legs, and feet. Histological
investigations indicate the development of phospholipoidosis, with scaly inclusions in hepatocyte
s, Schwann cells and other tissues which could point to the cause of peripheral neuropathy. The peripheral neuropathy is often but not always permanent. The risk of perhexiline toxicity is reduced by therapeutic drug monitoring (TDM).
The simplest way to rectify the problem of perhexiline toxicity is to stop administering the drug and allowing the plasma concentration to fall; once the concentration has reached the desired level resume the treatment at a lower dose. Most PMs should receive doses of no more than 50mg/week of perhexiline.
Australia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...
and New Zealand
New Zealand
New Zealand is an island country in the south-western Pacific Ocean comprising two main landmasses and numerous smaller islands. The country is situated some east of Australia across the Tasman Sea, and roughly south of the Pacific island nations of New Caledonia, Fiji, and Tonga...
. Perhexiline is thought to act by inhibiting mitochondrial carnitine palmitoyltransferase-1. This shifts myocardial metabolism from fatty acid to glucose utilisation which results in increased ATP production for the same O2 consumption and consequently increases myocardial efficiency. Its clinical use has been limited by its narrow therapeutic index
Therapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
and high inter- and intra-individual pharmacokinetic
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
variability. It was outlawed in many countries due to its adverse effects on poor metabolisers (PM). The product has been reintroduced for patients who have contraindications, or have not responded to, other treatments for angina.
Perhexiline metabolism
The major route of perhexiline metabolism in humans is hydroxylation by microsomal CYP2D6CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
. The two main metabolites of perhexiline are the cis and trans isomers of hydroxyperhexiline. CYP2D6 accounts for only a small percentage of total hepatic CYP450s but it is one of the main pathways for phase one metabolism of xenobiotic
Xenobiotic
A xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it. It can also cover substances which are present in much higher concentrations than are usual...
s. The limited availability of CYP2D6 means perhexiline metabolism is a saturable process.
Poor metabolisers
It is estimated that 7–10% of Caucasians are CYP2D6 PMs. Most PMs have an autosomal recessive polymorphismPolymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
in the CYP2D6 locus which results in the severely compromised metabolism of at least 25 drugs. It is believed that there are hundreds of potential polymorphism which will result in a PM, some result in functionally deficient CYP2D6, while others cause the absence of CYP2D6.
The Hydroxyperhexiline:Perhexiline ratio
Cis-hydroxyperhexiline is the primary determinant of perhexiline clearance and there is relatively little interindividual variability in the clearance of Cis-hydroxyperhexiline; therefore, the Cis-hydroxyperhexiline/perhexiline concentration ratio may be useful for optimizing individual patient treatment with the antianginal agent perhexiline. There is a segment of the population with very low hydroxyperhexiline/perhexiline ratios, this subpopulation contains those patients with the PM phenotype. It has been suggested that those with ratios ≤0.3 should be considered PMs; thus, providing a simple method for identifying PMs.Perhexiline toxicity
The adverse effects of perhexiline have been seen in more than 60% of recipients in some clinical trials. The most commonly reported adverse effects include headache, dizziness, nausea and vomiting. Plasma perhexiline concentrations as low as 0.6mg/L> are known to cause nausea and dizziness; however, perhexiline is also known to cause hepatotoxicityHepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
and peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
at plasma concentrations >0.6mg/L. The symptoms of peripheral neuropathy include weakness or sensory loss and pain in the arms, hand, legs, and feet. Histological
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
investigations indicate the development of phospholipoidosis, with scaly inclusions in hepatocyte
Hepatocyte
A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...
s, Schwann cells and other tissues which could point to the cause of peripheral neuropathy. The peripheral neuropathy is often but not always permanent. The risk of perhexiline toxicity is reduced by therapeutic drug monitoring (TDM).
The simplest way to rectify the problem of perhexiline toxicity is to stop administering the drug and allowing the plasma concentration to fall; once the concentration has reached the desired level resume the treatment at a lower dose. Most PMs should receive doses of no more than 50mg/week of perhexiline.