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Phenacetin metabolites

Various hydroxyl and amino derivatives of aromatic compounds are oxidized by peroxidases in the presence of hydrogen peroxide, yielding neutral or cation free radicals. Thus the phenacetin metabolites p-phenetidine (4-ethoxyaniline) and acetaminophen (TV-acetyl-p-aminophenol) were oxidized by LPO or HRP into the 4-ethoxyaniline cation radical and neutral V-acetyl-4-aminophenoxyl radical, respectively [198,199]. In both cases free radicals were detected by using fast-flow ESR spectroscopy. Catechols, Dopa methyl ester (dihydrox-yphenylalanine methyl ester), and 6-hydroxy-Dopa (trihydroxyphenylalanine) were oxidized by LPO mainly to o-semiquinone free radicals [200]. Another catechol derivative adrenaline (epinephrine) was oxidized into adrenochrome in the reaction catalyzed by HRP [201], This reaction can proceed in the absence of hydrogen peroxide and accompanied by oxygen consumption. It was proposed that the oxidation of adrenaline was mediated by superoxide. HRP and LPO catalyzed the oxidation of Trolox C (an analog of a-tocopherol) into phenoxyl radical [202]. The formation of phenoxyl radicals was monitored by ESR spectroscopy, and the rate constants for the reaction of Compounds II with Trolox C were determined (Table 22.1). [Pg.736]

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. [Pg.346]

FIGURE 4.7 Structures of the CYP1A2 substrates caffeine, phenacetin, their metabolites, and the CYP1A2 mechanism-based inhibitor, furafylline. [Pg.42]

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]. [Pg.137]

Acetaminophen (Tylenol) is the active metabolite of both phenacetin and acetanilide but has fewer toxic effects than either precursor. Phenacetin and acetanilide are no longer used therapeutically because they have been linked to methemoglobinemia. [Pg.314]

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. [Pg.812]

Acetaminophen is the active metabolite of phenacetin and is responsible for its analgesic effect. It is a weak COX-1 and COX-2 inhibitor in peripheral tissues and possesses no significant anti-inflammatory effects. [Pg.812]

Despite the resolving power of TLC-MS-MS, few applications in drug residue analysis have been reported. One application concerns the HPTLC-MS-MS analysis of a number of nonsteroidal anti-inflammatory drugs, including salicylic acid and its glycine conjugate salicylhippuric acid, diclofenac, indomethacin, naproxen, phenacetin, and ibuprofen (67). Another application describes the detection and identification of some of these compounds or their metabolites in urine by TLC-MS-MS (67). [Pg.730]

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). [Pg.100]

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... [Pg.155]

Figure 5.24 Metabolism of phenacetin showing the metabolite believed responsible for methemoglobinemia. Figure 5.24 Metabolism of phenacetin showing the metabolite believed responsible for methemoglobinemia.
The amount of futile acetylation observed for this compound in the rat, at ca. 7-10% for parent compound and metabolites, was less than that seen for phenacetin and similar to that found for paracetamol itself. The bulk of the radio-label was rapidly excreted in urine as practolol itself (albeit with 7-10% reacetylation) and the remainder as either the ring-hydroxylated metabolite or its glucuronide conjugate. As in previous examples, deuterated methanol was used in the mobile phase rather than methanol in order to be able to more easily observe the acetyl resonances of practolol and related compounds. [Pg.74]

Acetaminophen is the active metabolite of phenacetin and is responsible for its analgesic effect. It is a weak COX-1 and COX-2 inhibitor in peripheral tissues and possesses no significant antiinflammatory effects. Recent evidence suggests that acetaminophen may inhibit a third enzyme, COX-3, in the central nervous system. COX-3 appears to be a splice variant product of the COX-1 gene. [Pg.836]

Table 9.3 Phase II reactions. These normally produce pharmacologically inert metabolites but a few metabolites, such as N-acetylisoniazid and the sulphate conjugates of phenacetin, are toxic... Table 9.3 Phase II reactions. These normally produce pharmacologically inert metabolites but a few metabolites, such as N-acetylisoniazid and the sulphate conjugates of phenacetin, are toxic...
While the term biotransformation generally implies inactivation and detoxification, there are exceptional cases where a metabolite is more chemically active or more toxic than the parent compound. In these situations, the processes of bioactivation and biotoxification are said to have occurred, respectively. An example of bioactivation is the formation of the commonly used drug acetaminophen from phenacetin in the liver (see Figure 3.2). The latter drug was once widely used as an analgesic agent but because of kidney toxicity has been replaced by other more potent, less toxic substitutes including, of course, acetaminophen itself. In this particular bioactivation pathway the process occurs via normal oxidative dealkylation. [Pg.48]

Kiss and coworkers78,79 synthesized some minor D-glucosiduronic acid metabolites of phenacetin (isolated from the urine of patients sensitive to phenacetin), namely, the conjugates of 2-acetamido-5-eth-oxyphenol and 5-acetamido-2-ethoxyphenol (33 and 35) by the platinum-catalyzed oxidation of the corresponding /3-D-glucopyranosides, and by the Koenigs-Knorr condensation of 1 with the appropriate ni-... [Pg.91]

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. [Pg.292]

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. [Pg.312]

The chronic progression of events that lead to NSAID/analgesic related papillary necrosis are well known since the days of the first descriptions of chronic combined analgesics abuse nephropathy and the subsequent extensive investigations which defined the consequences of chronic (5-20 years) exposure of the kidney to high doses of analgesic combinations such as salicylate and acetaminophen (the metabolite of phenacetin) often with the addition of caffeine [106]. [Pg.434]

Relative to the fate in humans of the l pes of compounds just discu.s.sed. Brudie and Axelrod " " point out that acet-anilid and phenacetin are metabolized by two different routes. Acctaniiid is metabolized primarily to Af-acetyl-p-aminophenol and acetaminophen and only a small amount to aniline, which they showed to be the precursor of phenyl-hydroxylamine. the compound re.sponsible for methcmoglobin formation. Phenacetin is mostly dccthylated to acetaminophen. whereas a small amount is convened by dcacctylation top-phenetidinc. also responsible for methemoglobin formation. With both acetanilid and phenacetin. the metabolite acetaminophen is believed to be responsible for the analgesic activity. Because of the toxicity described above, both are no longer available, replaced primarily by acetaminophen. [Pg.762]

Koymans L, Van Lenthe JH, Donne-op Den Kelder GM, et al. Mechanisms of activation of phenacetin to reactive metabolites by cytochrome P-450 A theoretical study involving radical intermediates. Mol Pharmacol. 1990 37(3) 452-460. [Pg.122]


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See also in sourсe #XX -- [ Pg.115 , Pg.255 ]




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