Phenacetin, deacetylation

Methylation of the amido N-atom appears to reduce hydrolysis. Thus, the tertiary amide AT-methylphenacetin (4.116) was deacetylated by purified pig liver esterase at a rate much lower than observed for phenacetin [64],... 

The role of deacetylation in methemoglobinemia induced by acetanilide (4.101) and phenacetin (4.107) has been demonstrated. Indeed, concomitant i.p. administration of BNPP considerably reduced the hematotoxicity of these compounds [87]. Recent studies have shown that /V-hydroxyphenetidine (4.144), a metabolite of deacetylated phenacetin, is responsible for hemolysis and methemoglobin formation [88]. 

E. Bernhammer, K. Kirsch, Deacetylation of Phenacetin by Liver Esterase , Biochem. Pharmacol. 1965, 14, 863-871. 

G. S. Estus, J. J. Mieyal, Structure-Activity Relationship for Deacetylation of a Homologous Series of Phenacetin Analogs and Their V-Hydroxy Derivatives , Drug Metab. Dispos. 1983, 11, 471-476. 

Likewise, in certain case it was opposite. In human beings, phenacetin is generally free from toxic side effects, but in dogs it undergoes deacetylation. 

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). 

Toxic metabolites can occur in the same way that pharmacologically active and/or inactive metabolites are produced. For example, deacetylation of phenacetin yields / -phenetidine, the precursor of substances believed to be responsible for methaem-oglobinaemia. 

Aspirin also has the potential to increase acetaminophen nephropathy. Aspirin inhibits the cyclooxygenase component of prostaglandin H synthase without effect on the prostaglandin hydroperoxidase component, while salicylic acid (the deacetylated metabolite of aspirin) decreases renal glutathione concentrations. Thus, coadministration of aspirin with acetaminophen (or phenacetin) results in a synergistic nephrotoxicity. 

Phenacetin was mutagenic to Salmonella typhimur-ium bacteria when tested in the presence of a metabolic system derived from hamster but not mouse or rat liver. The urine from phenacetin-treated Chinese hamsters, but not that from rats, was mutagenic to bacteria. It is activated to direct-acting mutagens by deacetylation, occurring more frequently in hamsters than rats. Phenacetin induced chromosomal aberrations in Chinese hamster cells in vitro, but not DNA strand breaks in rat hepatocytes. It did not induce sex-linked recessive lethal mutations in Drosophila. 

Nicholls et al. have used NMR spectroscopy of urine combined with labelling with stable isotopes such as and to monitor the silent process of deacetylation and subsequent reacetylation (futile deactylation) in the rat as this has implications for the toxicity of paracetamoP and phenacetin. Hull et al. have monitored the metabolites of 5-fluorouracil in plasma and urine using NMR spectroscopy in patients receiving chemotherapy. Akira et al. have used H NMR to study the pharmacokinetics of benzoic... 

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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