Phenacetin metabolism

Pantuck EJ, Hsiao K-C, Kaplan SA, Kuntzman R, Conney AH. 1974. Effects of enzyme induction on intestinal phenacetin metabolism in the rat. J. Pharmacol. Exp. Ther. 191 45—52... 

Conney AH, Pantuck EJ, Hsiao K-C, Garland WA, Anderson KE, Alvares AP, Kappas A. 1976. Enhanced phenacetin metabolism in human subjects fed charcoal-broiled beef. Clin. Pharmacol. Ther. 20 633 12... 

Effect of cigarette smoking on phenacetin metabolism. Clin. Pharmacol. Then 15, 9-17. 

Dietary exposure to PAH was examined in more detail in a controlled CB beef feeding experiment in which each individual served as his own control. Two individuals exhibited measurable increases in PAH-DNA adduct levels while the two other individuals did not respond. This difference could be due to interindividual differences in constitutive or induced physiological parameters such as absorption, digestion, metabolism, excretion and DNA adduct formation and repair (11). Conney et al (12) demonstrated the induction of phenacetin metabolizing enzymes in human volunteers fed CB beef for four days. Variation in the Inducibllity of PAH metabolizing enzymes in hepatocytes and peripheral blood cells in individuals fed CB beef may explain some of the observed interindividual differences in this study. Other studies (13.14) have demonstrated a 3-10 fold variation in the ability of cultured human lymphocytes or monocytes to form B(a)P-DNA adducts after treatment with B(a)P. 

Pantuck EJ, Hsiao, K-C, Maggio A, Nakamura K, Kuntzman R, Conney AH (1974) Effect of cigarette smoking on phenacetin metabolism. Clin Pharmacol Ther 15 9-17... 

Figure 6 The NMR spectra of human urine taken 1 h after oral administration of ([1- C]ethoxy)phenacetin to a healthy subject (A) and to a patient with acute hepatitis (B). TSP, 3-(trimethylsilyl)propionate (internal standard). Adapted with permission ofThe Pharmaceutical Society of Japan from Kajiwara et al (1996) Studies on C phenacetin metabolism II. A combination of breath test and urine test of in vivo metabolites in the diagnosis of liver disease. Chemical Pharmaceutical Bulletin 44 1258-1260.

Anaemia Acute oxidative haemolysis may occur in glucose-6-phosphate dehydrogenase deficiency and rarely in individuals with a genetically determined abnormality of phenacetin metabolism (136, 189 ). Chronic haemolytic anaemia induced by phenacetin may result in splenomegaly (190 ). 

The metabolic formation of N-sulfonyloxy-N-acetyl-2-aminofluorene (N-sulfonyloxy-AAF) and its observed electrophilic reactivity, provided the first evidence for the importance of enzymatic conjugation reactions in chemical carcinogenesis (23,24). This reaction was shown to be catalyzed by PAPS-dependent sulfotrans-ferases that are located predominantly in liver cytosol and has been subsequently demonstrated for N-hydroxy arylamide metabolites of several other carcinogens, including N-acetyl-4-aminobiphenyl (AABP), benzidine, N-acetyl-2-aminophenanthrene and phenacetin. 

Deacylation may also be important in the carcinogenicity of arylamides. Phenacetin was found to exhibit higher mutagenicity in the Salmonella test system when incubated with hamster liver microsomes than with rat liver mi-crosomes. The metabolism of phenacetin in microsomal fractions revealed no significant species difference in /V-hydroxylalion, but rates of deacylation were much higher in rats than in hamsters. The species difference in mutagenicity observed may, therefore, be attributed to the differences in deacylat-ing activity between rat and hamster liver microsomes [96]. 

T. Nohmi, K. Yoshikawa, M. Nakadate, M. Ishidate Jr., Species Difference in the Metabolic Activation of Phenacetin by Rat and Hamster Liver Microsomes , Biochem. Bio-phys. Res. Commun. 1983, 110, 746-752. 

Generally, the liver is the center of drug metabolism, hence numerous drugs and methods to measure functional hepatic capacity are available. A host of these methods rely on the metabolic activity of cytochrome P450 enzymes, and some of the markers used include phenacetin, methacetin, trimethadione. 

Genetically determined defects in the phase I oxidative metabolism of debrisoquin, phenacetin, guanoxan, sparteine, phenformin, warfarin, and others have been reported (Table 4-4). The defects are apparently transmitted as autosomal recessive traits and may be expressed at any one of the multiple metabolic transformations that a chemical might undergo. 

Acetaminophen is one of the most important drugs used in the treatment of mild to moderate pain when an anti-inflammatory effect is not necessary. Phenacetin, a prodrug that is metabolized to acetaminophen, is more toxic than its active metabolite and has no rational indications. 

O-dealkylation. Aromatic methyl and ethyl ethers may be metabolized to give the phenol and corresponding aldehyde (Fig. 4.16), as illustrated by the de-ethylation of phenacetin (Fig. 4.20). Ethers with longer alkyl chains are less readily O-dealkylated, the preferred route being co-l-hydroxylation. 

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). 

The defective de-ethylation of phenacetin was discovered in a patient suffering methemoglobinemia after a reasonably small dose of the drug. This toxic effect was observed in a sister of the patient but not in other members of the family. The metabolism of phenacetin in the patient and in the sister was found to involve the production of large amounts of the normally minor metabolites 2-hydroxy phenacetin and 2-hydroxyphenetidine, with a concomitant reduction in the excretion of paracetamol, the major metabolic product of... 

Figure 5.24 Metabolism of phenacetin showing the metabolite believed responsible for methemoglobinemia.

In humans it has been demonstrated that increasing the ratio of protein to carbohydrate in the diet stimulates oxidation of antipyrine and theophylline, while changing the ratio of fat to carbohydrate had no effect. In related studies, humans fed charcoal-broiled beef (food high in polycyclic hydrocarbon content) for several days had significantly enhanced activities of CYPs 1A1 and 1A2, resulting in enhanced metabolism of phenacetin, theophylline, and antipyrine. Studies of this nature indicate that there is significant interindividual variability in these observed responses. 

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