Isoniazid acetylation

Isoniazid is acetylated to acetyl isoniazid by A-acetyl-transferase, an enzyme in fiver, bowel, and kidney. Individuals who are genetically rapid acetylators will have a higher ratio of acetyl isoniazid to isoniazid than will slow acetylators. Rapid acetylators were once thought to be more prone to hepatotoxicity, but this is not proved. The slow or rapid acetylation of isoniazid is rarely important clinically, although slow inactivators tend to develop peripheral neuropathy more readily. Metabolites of isoniazid and small amounts of unaltered drug are excreted in the urine within 24 hours of administration. 

In rapid acetylators isoniazid has a short half-life 1 hr)... 

Secondly, the rate of the enzymatic acetylation shows considerable inter-individual variation. This is illustrated in Fig. 2.30c. Shown are the plasma levels of unconjugated (i.e., not yet acetylated) isoniazid in the plasma, 6 hours after intake of a certain dosage 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... 

Rapid acetylator Isoniazid More prone to hepatitis... 

Acetyl transferease NAT2 Slow, rapid acetylators Isoniazid Sulfamethazine Procainamide Sufasalazine Paraminosalicylic acid Hydralazine Toxic neuritis, lupus erythematosus. (Slow acetylators)... 

Certain generic or metabolic abnormalities must be considered when prescribing antibiotics. A number of drugs (e.g., sulfonamides, nitrofurantoin, chloramphenicol, and nalidixic acid) may produce acute hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency. Patients who acetylate isoniazid rapidly may have subtherapeutic concentrations of the drug in plasma. 

The sulfones are distributed throughout total body water and are present in all tissues. They are retained in skin and muscle and especially in liver and kidney. The sulfones persist in the circulation for a long time because of reabsorption from the bile periodic interruption of treatment is advisable for this reason. Dapsone is acetylated in the liver by the same enzyme that acetylates isoniazid. Daily administration of50-100 mg results in serum levels exceeding the usual minimal inhibitory concentrations, even in rapid acetylators, in whom the serum t of dapsone is shorter than usual. 

Isoniazid oral 40 mg/kg (body weight) Plasma concentration of un-acetylated isoniazid at 6 hours Evans et al. (1960) Evans and White (1964). 

Acetyl-N-acetyltransferase - - isoniazid acetyl isoniazid - - N-acetyltransferase... 

Acetyl isoniazid or acetyl N -sulfamethazine Acetyl CoA Competitive... 

If standard doses of INH (isonicotinic hydrazide, isoniazid) with respect to body weight are administered to a randomly selected population, the plasma concentration of the drug a few hours later will show a bi- or trimodal distribution depending on the precision of the method used for INH determination. The decrease in INH-plasma levels is individually constant Variation is smaUer in identical than in dizygotic twins. All the drug is excreted in the urine as unchanged isoniazid. acetyl isoniazid, isonicotinic add and minor amounts of other metabolites. The percentage of inactive acetyl-INH in urine varies from 14-70% in relation to... 

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