Phenacetin metabolic pathways

The hydrolysis of some amides may be catalyzed by a liver microsomal carboxyl esterase, as is the case with phenacetin (Fig. 4.44). Hydrolysis of the acetylamino group, resulting in deacetylation, is known to be important in the toxicity of a number of compounds. For example, the deacetylated metabolites of phenacetin are thought to be responsible for its toxicity, the oxidation of hemoglobin to methemoglobin. This toxic effect occasionally occurs in subjects taking therapeutic doses of the drug and who have a deficiency in the normal pathway of metabolism of phenacetin to paracetamol. Consequently, more phenacetin is metabolized by deacetylation and subsequent oxidation to toxic metabolites (chap. 5, Fig. 24). 

Disposition in the Body. Acetaldehyde is a major intermediate metabolite of ethanol and is also a metabolite of metaldehyde, paraldehyde, and phenacetin. It undergoes further metabolism by oxidation to acetic acid and, eventually, to carbon dioxide and water. A minor pathway involves condensation with pyruvic acid to form acetoin. 

The discontinued analgesic phenacetin is metabolized to A/-hydroxyphenacetin and subsequently conjugated with sulfate. lite O-sulfate conjugate of A/-hydroxyphenacetin binds covalently to microsomal proteins. This pathway may represent one route leading to reactive intennediates that are responsible for the hepatotoxicity and nephrotoxicity... 

More recently it has become apparent that genetic factors also affect phase 1, oxidation pathways. Early reports of the defective metabolism of diphenylhydantoin in three families and of the defective deethylation of phenacetin in certain members of one family indicated a possible genetic component in microsomal enzyme-mediated reactions. Both these cases resulted in enhanced toxicity. Thus, diphenylhydantoin, a commonly used anticonvulsant, normally undergoes aromatic hydroxylation and the corresponding phenolic metabolite is excreted as a glucuronide (figure 7,35). Deficient... 

Some dmg interactions have been reported. An older example is that of low activity towards phenacetin favoring a potentially toxic secondary pathway, deacetylation followed by quinonei-mine formation and methemoglobinemia [96]. Furafylline was a drag candidate but was never developed because of its strong P450 1A2 inhibition and interference with caffeine metabolism [330]. High levels of P450 1A2 activity have also been associated with ineffectiveness of theophylline therapy (for asthma) [331,332]. 

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