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The New England Journal of Medicine Jul 1980
Topics: Analgesics; Headache; Humans; Phenacetin
PubMed: 7383094
DOI: No ID Found -
Journal of Clinical Pharmacology 1974
Topics: Acetaminophen; Adult; Biopharmaceutics; Dose-Response Relationship, Drug; Humans; Particle Size; Phenacetin; Powders; Surface-Active Agents; Tablets; Time Factors
PubMed: 4851431
DOI: 10.1002/j.1552-4604.1974.tb02323.x -
Xenobiotica; the Fate of Foreign... Jul 2006The metabolism of acetyl-labelled phenacetin-C2H3 was investigated in man following a single (150 mg) oral dose. Urine samples were collected at predose, 0-2 h and >2-4... (Comparative Study)
Comparative Study
Identification of phenacetin metabolites in human urine after administration of phenacetin-C2H3: measurement of futile metabolic deacetylation via HPLC/MS-SPE-NMR and HPLC-ToF MS.
The metabolism of acetyl-labelled phenacetin-C2H3 was investigated in man following a single (150 mg) oral dose. Urine samples were collected at predose, 0-2 h and >2-4 h post-dose, and samples from each time-point were then analysed directly using 1H-nuclear magnetic resonance (NMR) spectroscopy. The phenacetin metabolites acetaminophen (paracetamol) glucuronide, sulphate and the N-acetyl-L-cysteinyl conjugate were identified by this method, and all showed clear evidence of the loss of the original 2H3-acetyl label and its replacement with 1H3 (futile deacetylation). The observed percentage futile deacetylation by 1H-NMR spectroscopy was measured as approximately 20% in each metabolite (about 2% of the recovered dose). After sample preparation by solid-phase extraction on a C18 solid-phase extraction (SPE) cartridge, further profiling was performed using high-performance liquid chromatography/mass spectrometry-solid-phase extraction-nuclear magnetic resonance (HPLC/MS-SPE-NMR) confirming futile deacetylation had taken place as indicated by NMR spectroscopy on both the isolated acetaminophen glucuronide and L-cysteinyl-metabolites. Additional analysis by high-performance liquid chromatography-time-of-flight mass spectrometry (HPLC-ToF MS) identified further phenacetin metabolites, and from these data the mean percentage of futile deacetylation was measured as 31% +/- 2% for the acetylated phenacetin metabolites. A number of non-acetylated metabolites were also detected in the sample via HPLC-ToF MS. The results showed that phenacetin underwent a transient formation via a number of toxic intermediates to a much greater extent than had been observed in similar studies on acetaminophen. These results may contribute to the understanding of the analgesic nephropathy reported following chronic phenacetin consumption.
Topics: Acetylation; Animals; Chromatography, High Pressure Liquid; Humans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Phenacetin; Rats; Urine
PubMed: 16864507
DOI: 10.1080/00498250600711113 -
Journal of Pharmaceutical Sciences Jun 1975An automated high-pressure liquid chromatographic (HPLC) method for the separation and determination of aspirin, phenacetin, and caffeine in pharmaceutical dosage forms...
An automated high-pressure liquid chromatographic (HPLC) method for the separation and determination of aspirin, phenacetin, and caffeine in pharmaceutical dosage forms is descreibed. Separation of these compounds for quantitation is achieved on a controlled pore glass support, utilizing a mixture of acetic acid and chloroform as the mobile phase. The method is specific, accurate, and simple and provides for the quantitation of each chromatogram in a continuous fashion every 7 min. HPLC separation of other analgesics was studied on a spherical siliceous support. The feasibility of determining free salicylic acid in analgesics also was established.
Topics: Aspirin; Autoanalysis; Caffeine; Chromatography; Phenacetin
PubMed: 1133721
DOI: 10.1002/jps.2600640633 -
Clinical Nephrology 1974
Topics: Age Factors; Antipyrine; Caffeine; Female; Humans; Kidney Failure, Chronic; Kidney Neoplasms; Kidney Pelvis; Male; Papilloma; Phenacetin; Salicylates; Sex Factors; Substance-Related Disorders; Sweden; Time Factors
PubMed: 4847128
DOI: No ID Found -
Cancer Research Mar 1987The metabolism and binding of the analgetic drug [ring-3H]phenacetin in the nasal mucosa were studied in vitro and in vivo in male Sprague-Dawley rats. As shown by...
The metabolism and binding of the analgetic drug [ring-3H]phenacetin in the nasal mucosa were studied in vitro and in vivo in male Sprague-Dawley rats. As shown by whole-body and light microscopic autoradiography there was an irreversible binding of metabolites to the glands of Bowman in the olfactory mucosa after high but not after low doses of [3H]phenacetin. In the other tissues, the distribution of radioactivity was not changed when the dose was increased. Autoradiography of [3H]-acetaminophen showed no preferential uptake of radioactivity in the olfactory mucosa. At incubation of nasal septa with [3H]phenacetin in vitro, a binding of metabolites to the glands of Bowman was observed indicating that the metabolism occurred in situ. In rats, glutathione (GSH) depleted by pretreatment with phorone, there was a binding to the glands of Bowman in the olfactory mucosa also after a trace dose of [3H]phenacetin. Addition of GSH decreased the irreversible binding of [3H]phenacetin metabolites that occurred in 9000 X g nasal mucosa supernatants incubated with [3H]phenacetin. There was a moderate decrease in the level of nonprotein sulfhydryl groups, mainly GSH, in the olfactory mucosa after administration of 100-300 mg/kg phenacetin. Collectively, these data suggest that phenacetin is metabolized and subsequent to GSH depletion, bound preferentially in the glands of Bowman. The data also suggest that in situ metabolic activation and binding of phenacetin in the rat nasal mucosa at high doses may play a role in the pathogenesis of the nasal tumors induced by high doses of phenacetin in the rat.
Topics: Animals; Autoradiography; Biotransformation; Dose-Response Relationship, Drug; In Vitro Techniques; Ketones; Male; Nasal Mucosa; Phenacetin; Rats; Rats, Inbred Strains; Sulfhydryl Compounds; Tissue Distribution; Tritium
PubMed: 3815346
DOI: No ID Found -
Drug Metabolism and Disposition: the... 1979
Topics: Acetaminophen; Animals; Biotransformation; Hydrolysis; Injections, Intraperitoneal; Injections, Intravenous; Kinetics; Male; Phenacetin; Portal Vein; Rats; Time Factors
PubMed: 43221
DOI: No ID Found -
Drug Metabolism and Disposition: the... 1976Hamster liver microsomes have been shown to catalyze the N-hydroxylation of phenacetin. The reaction, which requires oxygen and NADPH, is inhibited by a carbon...
Hamster liver microsomes have been shown to catalyze the N-hydroxylation of phenacetin. The reaction, which requires oxygen and NADPH, is inhibited by a carbon monoxide/oxygen atmosphere, indicating that it is catalyzed by a cytochrome P-450-dependent mixed-function oxidase. The N-hydroxyphenacetin can be further metabolized by the microsomes, and the reaction is inhibited by phenacetin.
Topics: Animals; Cobalt; Cricetinae; Hot Temperature; Hydroxylation; In Vitro Techniques; Male; Mass Spectrometry; Mesocricetus; Methylcholanthrene; Microsomes, Liver; NADP; Phenacetin; Phenobarbital; Piperonyl Butoxide
PubMed: 10141
DOI: No ID Found -
Journal of Medicinal Chemistry Aug 1986N-Acetyl-p-benzoquinone imine (4) can be detected by UV spectrophotometry and HPLC during the hydrolysis of N-(pivaloyloxy)phenacetin (3c). This material serves as a...
N-Acetyl-p-benzoquinone imine (4) can be detected by UV spectrophotometry and HPLC during the hydrolysis of N-(pivaloyloxy)phenacetin (3c). This material serves as a model for the sulfate and glucuronide conjugates (3a and 3b) of N-hydroxyphenacetin (2). Direct detection of 4 during the hydrolysis of 3a and 3b is precluded by the extreme instability of 3a and the very slow hydrolysis of 3b. Our data show that greater than 90% of the hydrolysis of 3c proceeds through the intermediate 4 at all pH values in the range 1.0-8.0. All our results indicate that 4 is produced through a nitrenium ion mechanism. Many of the differences in the hydrolysis reactions of 3b and 3c can be explained in terms of a mechanism involving tight and solvent-separated nitrenium ion pairs. Other differences may be due to a homolysis pathway, which is more important for the material with the poorer leaving group (3b).
Topics: Benzoquinones; Chromatography, High Pressure Liquid; Hydrogen-Ion Concentration; Imines; Kinetics; Magnetic Resonance Spectroscopy; Mathematics; Phenacetin; Spectrophotometry, Ultraviolet
PubMed: 3735311
DOI: 10.1021/jm00158a018 -
Clinical Pharmacology and Therapeutics 1968
Comparative Study
Topics: Acetaminophen; Animals; Chromatography, Thin Layer; Dogs; Humans; Kidney Tubules; Phenacetin; Pigments, Biological; Rats
PubMed: 5676801
DOI: 10.1002/cpt196895605