Phenelzine acetylation

Examples of monoamine oxidase inhibitors are phenelzine, tranylcypromine, isocarboxazid and mo-clobemide. They are indicated for atypical depression. Changes in the neurotransmitter levels are seen in several days but the clinical effect may lag by several weeks. Phenelzine is a non-selective hydrazine-type monoamine oxidase inhibitor while the also non-selective inhibitor tranylcypromine is of the non-hydrazine-type. Phenelzine, tranylcypromine and isocarboxazid are irreversible inhibitors. Phenelzine is partly metabolized by acetylation and slow acetylators are more prone to toxicity. It has anxiolytic properties and superior efficiacy in treating severe anxiety. 

Although the half-life of an MAOI is short (hours), the half-life of MAO inhibition is about 2 weeks because it takes that long for the new enzyme to be synthesized. Some have speculated that phenelzine may be metabolized by acetylation and that there are two hereditary types (i.e., slow and fast acetylators), with slow acetylators presumably having a greater degree of MAO inhibition. There is limited support for the theory that slow acetylators have a better response, whereas other investigators find no difference (179). More importantly, there is no evidence that phenelzine is indeed acetylated. 

Johnstone EC. The relationship between acetylator status and inhibition of monoamine oxidase, excretion of free drug and antidepressant response in depressed patients on phenelzine. Psychopharmacoiogia 1976 46 289-294. 

The different MAOIs are metabolized via different pathways but tend to have extensive first-pass effects that may substantially decrease bioavailability. Tranylcypromine is ring hydroxylated and /V-acetylated, whereas acetylation appears to be a minor pathway for phenelzine. Selegiline is /V-demethylated and then hydroxylated. The MAOIs are well absorbed from the gastrointestinal tract. 

Acetylator status Refers to ability to acetylate organic compounds in the liver. A rapid acetylator refers to an individual whose N-acetyl transferase is hyperactive. Such individuals are more likely to require larger doses of drugs such as phenelzine. Conversely, slow acetylators have a genetically linked deficit in N-acetyl transferase and therefore require a lower dose of the drug. 

Slow acetylator Isoniazid Hydralazine, procainamide Phenelzine, sulfasalazine Increased incidence of peripheral neuropathy SLE-like syndrome and more prone to phenytoin toxicity Increased incidence of SLE-like syndrome More prone to side effects... 

The biotransformation of hydrazine and hydrazide derivatives also proceeds by acetylation. The antihypertensive hydralazine (Apresoline) " ""and the MAO inhibitor phenelzine (Nardil) " are two representative hydrazine compounds that are metabolized by this pathway. The initially formed N-acetyl derivative of hydralazine is unstable and cyclizes intramolecularly to form 3-methyl-s-triazolo 3.4-a phtha-lazine as the major isolable hydralazine metabolite in humans. " The antituberculosis drug isoniazid or isonicoli-nic acid hydrazide (INH) is metabolized extensively to N-acetylisoniazid. " ... 

Acetylation of drugs is also associated with genetically determined interindividual and interethnic differences. Differences in isoniazid toxicity between Asians and Caucasians are due to acetylation enzyme polymorphism. The majority (78%-93%) of Chinese and East Asians are fast acetylators, whereas only 50% of whites and African Americans are fast acetylators (Weber 1987). This is clinically important, because several psychoactive compounds (e.g., caffeine, clonazepam, nitrazepam, and phenelzine) are metabolized through acetylation (Sjoqvist et al. 1997). 

Monoamine oxidase inhibitors are not commonly prescribed to Asians, because many traditional Asian foods, including fermented bean curd, soy sauce, and fermented soybeans, contain relatively high levels of tyramine (a pressor amine), ranging from 0.02 to 43.0 pmol/g (Sung et al. 1986). Because the vast majority of Asians are fast acetylators (Whitford 1978), the metabolism of phenelzine may be increased in Asians, resulting in higher dose requirements than in Caucasians. 

Harris AL, McIntyre N. Interaction of phenelzine and nitrazepam in a slow acetylator. BrJ Clin Pharmacol (1981) 12, 254-5. 

Phenelzine in Urine Assay and Relation to Acetylator Status Br. J. Clin. Pharmacol. 3(4) 633-637... 

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