phenacetin

Summary

Summary: A phenylacetamide that was formerly used in ANALGESICS but nephropathy and METHEMOGLOBINEMIA led to its withdrawal from the market. (From Smith and Reynard, Textbook of Pharmacology,1991, p431)

Top Publications

  1. Michielsen P. In memoriam 'analgesic nephropathy' (circa 1972-2006). Nephrol Dial Transplant. 2007;22:999-1001 pubmed
  2. Mihatsch M, Khanlari B, Brunner F. Obituary to analgesic nephropathy--an autopsy study. Nephrol Dial Transplant. 2006;21:3139-45 pubmed
  3. Abbott F, Hellemans K. Phenacetin, acetaminophen and dipyrone: analgesic and rewarding effects. Behav Brain Res. 2000;112:177-86 pubmed
    The antinociceptive and rewarding effects of phenacetin, a mild analgesic with abuse liability, were compared with those of acetaminophen, dipyrone and indomethacin in the formalin and conditioned place preference tests...
  4. DeVore N, Smith B, Urban M, Scott E. Key residues controlling phenacetin metabolism by human cytochrome P450 2A enzymes. Drug Metab Dispos. 2008;36:2582-90 pubmed publisher
    ..b>Phenacetin and 4-aminobiphenyl were identified as substrates of human cytochromes P450 1A2 and 2A13 but not of CYP2A6...
  5. Nouri Nigjeh E, Bischoff R, Bruins A, Permentier H. Electrochemical oxidation by square-wave potential pulses in the imitation of phenacetin to acetaminophen biotransformation. Analyst. 2011;136:5064-7 pubmed publisher
    ..Here, we present electrochemical O-dealkylation of phenacetin to acetaminophen by square-wave potential pulses consisting of consecutive sub-second oxidation and reduction ..
  6. Michielsen P, Heinemann L, Mihatsch M, Schnülle P, Graf H, Koch K. Non-phenacetin analgesics and analgesic nephropathy: clinical assessment of high users from a case-control study. Nephrol Dial Transplant. 2009;24:1253-9 pubmed publisher
    ..1] found no increased risk of end-stage renal disease (ESRD) in users of combined or single formulations of phenacetin-free analgesics...
  7. Donato M, Hallifax D, Picazo L, Castell J, Houston J, Gomez Lechon M, et al. Metabolite formation kinetics and intrinsic clearance of phenacetin, tolbutamide, alprazolam, and midazolam in adenoviral cytochrome P450-transfected HepG2 cells and comparison with hepatocytes and in vivo. Drug Metab Dispos. 2010;38:1449-55 pubmed publisher
    ..The kinetics of metabolite formation from phenacetin, tolbutamide, and alprazolam and midazolam, selected as substrates probes for CYP1A2, CYP2C9, and CYP3A4, ..
  8. Watanabe A, Fukami T, Takahashi S, Kobayashi Y, Nakagawa N, Nakajima M, et al. Arylacetamide deacetylase is a determinant enzyme for the difference in hydrolase activities of phenacetin and acetaminophen. Drug Metab Dispos. 2010;38:1532-7 pubmed publisher
    b>Phenacetin was withdrawn from the market because it caused renal failure in some patients. Many reports indicated that the nephrotoxicity of phenacetin is associated with the hydrolyzed metabolite, p-phenetidine...
  9. Jian T, He J, He G, Feng E, Li H, Bai M, et al. Scutellarin inhibits cytochrome P450 isoenzyme 1A2 (CYP1A2) in rats. Phytother Res. 2012;26:1226-30 pubmed publisher
    ..decreased the clearance (CL), and increased the T(1/2) (at 15, 30?mg/kg, i.p.), it did not affect the V(d) of phenacetin. Scutellarin treatment (at 5, 15, 30?mg/kg, i.p.) increased the AUC(0-?) by 14.3%, 67.3% and 159...

More Information

Publications62

  1. Josse R, Aninat C, Glaise D, Dumont J, Fessard V, Morel F, et al. Long-term functional stability of human HepaRG hepatocytes and use for chronic toxicity and genotoxicity studies. Drug Metab Dispos. 2008;36:1111-8 pubmed publisher
  2. Weaver R, Graham K, Beattie I, Riley R. Cytochrome P450 inhibition using recombinant proteins and mass spectrometry/multiple reaction monitoring technology in a cassette incubation. Drug Metab Dispos. 2003;31:955-66 pubmed
    ..This method uses combined substrates (phenacetin, diclofenac, S-mephenytoin, bufuralol, and midazolam) with combined recombinant P450 enzymes (CYP1A2, 2C9, 2C19, ..
  3. Jensen C, Jollow D. The role of N-hydroxyphenetidine in phenacetin-induced hemolytic anemia. Toxicol Appl Pharmacol. 1991;111:1-12 pubmed
    b>Phenacetin is well known to cause hemolytic anemia and methemoglobinemia in humans...
  4. Rolim C, Porta V, Storpirtis S. Quantitation of nimesulide in human plasma by high-performance liquid chromatography with ultraviolet absorbance detection and its application to a bioequivalence study. Arzneimittelforschung. 2007;57:537-41 pubmed
    ..After the plasma samples were extracted with 6.0 ml of dichloromethane containing the internal standard phenacetin 2 microg/ml in methanol, the analysis of the nimesulide level in the plasma samples was carried out using a ..
  5. Wang Y, Liu S. [Determination of three components in compound chlorophenamine tablet by iterative target transformation factor analysis]. Guang Pu Xue Yu Guang Pu Fen Xi. 2001;21:254-5 pubmed
    b>Phenacetin, amidopyrine and caffeine in compound chlorophenamine tablet were determined by iterative target transformation factor analysis. The results are satisfactory. The mean recoveries and relative standard deviation are 100.4%, 0...
  6. Schnuelle P, van der Woude F. Analgesics and renal disease in the postphenacetin era. Am J Kidney Dis. 2003;42:385-7 pubmed
  7. Sy S, Tang B, Pastrakuljic A, Roberts E, Kalow W. Detailed characterization of experimentally derived human hepatic CYP1A1 activity and expression using differential inhibition of ethoxyresorufin O-deethylation by fluvoxamine. Eur J Clin Pharmacol. 2001;57:377-86 pubmed
    ..To characterize the distribution of mathematically derived human hepatic CYP1A1 activity using differential inhibition of ethoxyresorufin O-deethylation (EROD) by fluvoxamine...
  8. Whiterock V, Morgan D, Lentz K, Orcutt T, Sinz M. Phenacetin pharmacokinetics in CYP1A2-deficient beagle dogs. Drug Metab Dispos. 2012;40:228-31 pubmed publisher
    b>Phenacetin is widely used as an in vitro probe to measure CYP1A2 activity across species...
  9. Kudo S, Umehara K, Hosokawa M, Miyamoto G, Chiba K, Satoh T. Phenacetin deacetylase activity in human liver microsomes: distribution, kinetics, and chemical inhibition and stimulation. J Pharmacol Exp Ther. 2000;294:80-8 pubmed
    Microsomal and cytosolic phenacetin deacetylase activities were examined in human liver and kidneys. Kinetic properties of the activities were also studied in human liver microsomes...
  10. Kiersch T, Minić M. The onset of action and the analgesic efficacy of Saridon (a propyphenazone/paracetamol/ caffeine combination) in comparison with paracetamol, ibuprofen, aspirin and placebo (pooled statistical analysis). Curr Med Res Opin. 2002;18:18-25 pubmed
    ..The results of this pooled analysis of eight studies should be confirmed in a double-blind study, since seven of the studies included in this analysis were single blind...
  11. Sharma K, Kandaswamy M, Mithra C, Meena A, Giri S, Rajagopal S, et al. Highly sensitive LC-MS/MS-ESI method for simultaneous quantitation of albendazole and ricobendazole in rat plasma and its application to a rat pharmacokinetic study. Biomed Chromatogr. 2012;26:247-55 pubmed publisher
    ..for simultaneous quantification of albenadazole (ABZ) and ricobendazole (RBZ) in rat plasma (50 ?L) using phenacetin as an internal standard (IS). Simple protein precipitation was used to extract ABZ and RBZ from rat plasma...
  12. Gago Dominguez M, Yuan J, Castelao J, Ross R, Yu M. Regular use of analgesics is a risk factor for renal cell carcinoma. Br J Cancer. 1999;81:542-8 pubmed
    b>Phenacetin-based analgesics have been linked to the development of renal pelvis cancer and renal cell carcinoma (RCC)...
  13. Dou Y, Qu N, Wang B, Chi Y, Ren Y. Simultaneous determination of two active components in compound aspirin tablets using principal component artificial neural networks (PC-ANNs) on NIR spectroscopy. Eur J Pharm Sci. 2007;32:193-9 pubmed
    A method for simultaneous, non-destructive analysis of aspirin and phenacetin in compound aspirin tablets with different concentrations has been developed by principal component artificial neural networks (PC-ANNs) on near-infrared (NIR) ..
  14. Nicholls A, Wilson I, Godejohann M, Nicholson J, Shockcor J. 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. Xenobiotica. 2006;36:615-29 pubmed
    The metabolism of acetyl-labelled phenacetin-C2H3 was investigated in man following a single (150 mg) oral dose...
  15. Shimada T, Mimura M, Inoue K, Nakamura S, Oda H, Ohmori S, et al. Cytochrome P450-dependent drug oxidation activities in liver microsomes of various animal species including rats, guinea pigs, dogs, monkeys, and humans. Arch Toxicol. 1997;71:401-8 pubmed
    ..oxidation activities catalyzed by liver microsomes of these animal species using eleven P450 substrates such as phenacetin, coumarin, pentoxyresorufin, phenytoin, S-mephenytoin, bufuralol, aniline, benzphetamine, ethylmorphine, ..
  16. Hu L, Xu W, Zhang X, Su J, Liu X, Li H, et al. In-vitro and in-vivo evaluations of cytochrome P450 1A2 interactions with nuciferine. J Pharm Pharmacol. 2010;62:658-62 pubmed publisher
    ..The effects of nuciferine, a major active aporphine alkaloid from the leaves of Nelumbo nucifera Gaertn, on a cytochrome P450 1A2 (CYP1A2) probe substrate were investigated in vitro and in vivo...
  17. Xiong W, Jin H, Li S, Jin J, Ji B, Yu C. Evaluating human liver reserve function by measuring serum concentrations of phenacetin and its metabolites. J Dig Dis. 2010;11:358-63 pubmed publisher
    To evaluate human liver reserve function (LRF) by a simple and efficient method for measuring serum concentrations of phenacetin and its metabolites.
  18. Nagata Y, Masuda A. Bladder tumor associated with phenacetin abuse: a case report and a review of the literature. Tokai J Exp Clin Med. 2007;32:86-9 pubmed
    We herein report the case of a bladder tumor in an 85-year-old man who had been engaged in phenacetin abuse. He had been taking phenacetin owing to migraine headaches since he was 45 year of age...
  19. Thommes M, Kleinebudde P. Properties of pellets manufactured by wet extrusion/spheronization process using kappa-carrageenan: effect of process parameters. AAPS PharmSciTech. 2007;8:E95 pubmed publisher
    ..These parameters were varied systematically in a 2(4) full factorial design. In addition, 4 drugs--phenacetin, chloramphenicol, dimenhydrinate, and lidocaine hydrochloride--were investigated under constant process ..
  20. Wang X, Chen X, Chen M, Hu G, Ma J, Pan J, et al. Assessment of effects of chronic hydrogen sulfide poisoning on cytochrome P450 isoforms activity of rats by cocktail approach. Biol Pharm Bull. 2013;36:1627-33 pubmed
    ..CYP2B6 and CYP2D6, which were reflected by the changes of pharmacokinetic parameters of 4 specific probe drugs phenacetin, tolbutamide bupropion and metroprolol, respectively...
  21. Garcia Lopez P, Martinez Cruz A, Guizar Sahagun G, Castaneda Hernandez G. Acute spinal cord injury changes the disposition of some, but not all drugs given intravenously. Spinal Cord. 2007;45:603-8 pubmed
    ..Experimental laboratory investigations in paraplegic rats...
  22. Qiu H, Su G, Tang X. [Tissue-like cultures of rat hepatocytes in study of phase I and phase II drug metabolism]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2006;35:541-6 pubmed
    ..To investigate phase I and phase II enzyme activities in drug metabolism with tissue-like cultures of rat hepatocytes...
  23. Szutowski M, Zalewska K, Jadczak M, Marek M. In vivo effect of diallyl sulfide and cimetidine on phenacetin metabolism and bioavailability in rat. Acta Biochim Pol. 2002;49:249-56 pubmed
    ..P450 2E1 inhibitor and cimetidine--a cytochrome P450 2C6 and 2C11 inhibitor on rat serum concentration of phenacetin and its metabolite acetaminophen...
  24. Smith C, Jensen B, Wilson I, Abou Shakra F, Crowther D. High-performance liquid chromatography/inductively coupled plasma mass spectrometry and tandem mass spectrometry for the detection of carbon-containing compounds. Rapid Commun Mass Spectrom. 2004;18:1487-92 pubmed
    ..enabled the detection of 86 micromol for 13C-triple-labelled caffeine and 79 micromol for 13C-double-labelled phenacetin. The sensitive detection of 12C-compounds with 13C-enriched methanol as organic modifier proved impractical due ..
  25. Swanson J, English J. Serum sickness-like reaction to Pamabrom. J Drugs Dermatol. 2006;5:284-6 pubmed
    ..An urticarial eruption, with systemic complaints consistent with a serum sickness-like reaction, attributed to Pamabron is described. A review of the literature concerning Pamabron and dermatology is discussed...
  26. Eugster H, Probst M, Wurgler F, Sengstag C. Caffeine, estradiol, and progesterone interact with human CYP1A1 and CYP1A2. Evidence from cDNA-directed expression in Saccharomyces cerevisiae. Drug Metab Dispos. 1993;21:43-9 pubmed
    ..Inhibition studies with caffeine, phenacetin, 17 beta-estradiol, and progesterone as inhibitors of the CYP1A1 and CYP1A2 catalyzed O-deethylation of 7-..
  27. Sharma K, Police A, Kumar A, Pawar G, Giri S, Rajagopal S, et al. Development and validation of an LC-MS/MS-ESI method for the determination of lorglumide, a CCK-1 antagonist in mouse plasma: application to a pharmacokinetic study. Biomed Chromatogr. 2012;26:833-8 pubmed publisher
    ..The assay procedure involves extraction of lorglumide and phenacetin (internal standard, IS) from mouse plasma with simple protein precipitation...
  28. Lee W, Zhou X, Or P, Kwan Y, Yeung J. Tanshinone I increases CYP1A2 protein expression and enzyme activity in primary rat hepatocytes. Phytomedicine. 2012;19:169-76 pubmed publisher
    ..The ethanolic extract of Danshen roots (containing mainly tanshinones) inhibited CYP1A2-catalyzed phenacetin O-deethylation (IC(50)=24...
  29. Qu Z, Li X, Liu H, He P, Zhang X, Wu M. Impaired clearance of phenacetin in hepatic cirrhosis and fibrosis. Int J Clin Pharmacol Ther. 2007;45:55-62 pubmed
    CYP450 1A2 is constitutively expressed in liver. Phenacetin O-de-ethylation is a marker reaction for CYP450 1A2 activity...
  30. Vickers A, Zollinger M, Dannecker R, Tynes R, Heitz F, Fischer V. In vitro metabolism of tegaserod in human liver and intestine: assessment of drug interactions. Drug Metab Dispos. 2001;29:1269-76 pubmed
    ..M29.0, the main circulating metabolite, did not demonstrate any inhibitory potential toward cytochrome P450 enzymes in vitro. Therefore, clinically relevant metabolic drug interactions with tegaserod seem unlikely...
  31. Vad N, Kudugunti S, Graber D, Bailey N, Srivenugopal K, Moridani M. Efficacy of acetaminophen in skin B16-F0 melanoma tumor-bearing C57BL/6 mice. Int J Oncol. 2009;35:193-204 pubmed
    ..Mice receiving APAP day 1 through 13 post melanoma cell inoculation showed tumor size growth inhibition by 11+/-7, 33+/-9, 36+/-20 and 44+/-28%, respectively...
  32. Moyad M. Review of potential risk factors for kidney (renal cell) cancer. Semin Urol Oncol. 2001;19:280-93 pubmed
  33. Zhou X, Wang Y, Hu T, Or P, Wong J, Kwan Y, et al. Enzyme kinetic and molecular docking studies for the inhibitions of miltirone on major human cytochrome P450 isozymes. Phytomedicine. 2013;20:367-74 pubmed publisher
    ..Taken together, CYPs inhibitions of miltirone were weaker than dihydrotanshinone, but stronger than cryptotanshinone, tanshinone I and tanshinone IIA...
  34. Howe P, Ament Z, Knowles K, Griffin J, Wright J. Combined use of filtered and edited 1 H NMR spectroscopy to detect 13 C-enriched compounds in complex mixtures. NMR Biomed. 2012;25:1217-23 pubmed publisher
    ..The theory underlying the approach is described and the method is demonstrated by the detection of sub-microgram amounts of (13) C-enriched phenacetin in crude extracts of hepatocyte microsomes.
  35. Guengerich F, Parikh A, Yun C, Kim D, Nakamura K, Notley L, et al. What makes P450s work? Searches for answers with known and new P450s. Drug Metab Rev. 2000;32:267-81 pubmed
    ..For phenacetin O-deethylation, the E225I mutant had kcat 6x > wild type; D320A had kcat 1/10x < wild type (and Km 15 x &..
  36. Zuleger S, Lippold B. Polymer particle erosion controlling drug release. I. Factors influencing drug release and characterization of the release mechanism. Int J Pharm. 2001;217:139-52 pubmed
  37. Boobis A, Kahn G, Whyte C, Brodie M, Davies D. Biphasic O-deethylation of phenacetin and 7-ethoxycoumarin by human and rat liver microsomal fractions. Biochem Pharmacol. 1981;30:2451-6 pubmed
    ..and rat liver microsomal fractions exhibit non-linear Michaelis-Menten kinetics in the O-deethylation of both phenacetin and 7-ethoxycoumarin...
  38. Hu M, Krausz K, Chen J, Ge X, Li J, Gelboin H, et al. Identification of CYP1A2 as the main isoform for the phase I hydroxylated metabolism of genistein and a prodrug converting enzyme of methylated isoflavones. Drug Metab Dispos. 2003;31:924-31 pubmed
    ..The interaction studies showed that genistein inhibited formation of acetaminophen from phenacetin with an IC50 value of 16 microM...
  39. Nista E, Fini L, Armuzzi A, Candelli M, Zocco M, Cazzato I, et al. 13C-breath tests in the study of microsomal liver function. Eur Rev Med Pharmacol Sci. 2004;8:33-46 pubmed
    ..The other group is composed of substrates with flow dependent metabolism like methacetin, phenacetin, erythromycin...
  40. Alqaradawi S, Nour E. Spectroscopic investigation of the novel charge-transfer complex [(phen)(TCNE)(12)] formed in the reaction of phenacetin with tetracyanoethylene. Spectrochim Acta A Mol Biomol Spectrosc. 2005;62:578-81 pubmed
    The charge-transfer (CT) interaction of the electron donor phenacetin (phen) and the pi-electron acceptor tetracyanoethylene (TCNE) has been studied in CH(2)Cl(2)...
  41. Alcorn J, Elbarbry F, Allouh M, McNamara P. Evaluation of the assumptions of an ontogeny model of rat hepatic cytochrome P450 activity. Drug Metab Dispos. 2007;35:2225-31 pubmed
    ..chlorzoxazone 6-hydroxylation and methoxyresorufin O-dealkylation, and V(max) estimates for p-nitrophenol and phenacetin hydroxylations, respectively...
  42. Shimizu K, Ando M, Nakayama Y. Characterization of tableting using the OSDRC system. Pharm Res. 2007;24:1902-9 pubmed
    ..We compared the compression properties and characteristics of tablets obtained using the OSDRC system (method (OSDRC)) and conventional compression methods including multi-layer compression with a pharmaceutical powder...
  43. Tanaka N, Miyasho T, Shinkyo R, Sakaki T, Yokota H. cDNA cloning and characterization of feline CYP1A1 and CYP1A2. Life Sci. 2006;79:2463-73 pubmed
    ..Because feline CYP1A2 had a higher K(m) for phenacetin O-deethylase activity with acetaminophen, which cannot be conjugated with glucuronic acid due to UDP-..
  44. Kankuri E, Solatunturi E, Vapaatalo H. Effects of phenacetin and its metabolite p-phenetidine on COX-1 and COX-2 activities and expression in vitro. Thromb Res. 2003;110:299-303 pubmed
    ..present study was aimed to test the possible cyclooxygenase (COX)-1/COX-2 selectivity of the old analgesic drug phenacetin and its metabolite p-phenetidine, which exhibits high renal toxicity...
  45. Kojima K, Tamaki M, Maeda S, Hori T, Nishino Y, Deguchi T. [A case of renal pelvic tumor due to phenacetin abuse]. Hinyokika Kiyo. 2002;48:293-6 pubmed
    A 65-year-old female had been taking analgesics containing phenacetin, because of severe headaches since 1958. The total dose of phenacetin that she had taken was calculated to be 8.0 kg...
  46. Hu Y, Yao T. Inhibitive effect of diphenytriazol on rat cytochrome P450 enzyme in vitro. Pharmazie. 2009;64:455-60 pubmed
    ..on CYP was investigated by coincubating diphenytriazol with the specific CYP1A substrates, ethoxyresorufin and phenacetin, in microsome induced by beta-naphthoflavone, with the specific CYP2B substrates, pentoxyresorufin and ..
  47. Vail R, Homann M, Hanna I, Zaks A. Preparative synthesis of drug metabolites using human cytochrome P450s 3A4, 2C9 and 1A2 with NADPH-P450 reductase expressed in Escherichia coli. J Ind Microbiol Biotechnol. 2005;32:67-74 pubmed
    ..metabolites of the anabolic steroid testosterone, the anti-inflammatory agent diclofenac and the analgesic agent phenacetin, were generated using 3A4, 2C9 and 1A2, respectively...
  48. Lofgren S, Hagbjork A, Ekman S, Fransson Steen R, Terelius Y. Metabolism of human cytochrome P450 marker substrates in mouse: a strain and gender comparison. Xenobiotica. 2004;34:811-34 pubmed
    ..Thirteen human CYP probe substrates (phenacetin, coumarin, 7-ethoxy-4-trifluoromethyl coumarin, amiodarone, paclitaxel, diclofenac, S-mephenytoin, bufuralol, ..
  49. Kamei T, Aoyama T, Tanaka C, Nagashima T, Aoyama Y, Hayashi H, et al. Quantitation of pyrrole-imidazole polyamide in rat plasma by high-performance liquid chromatography coupled with UV detection. J Biomed Biotechnol. 2012;2012:715928 pubmed publisher
    ..50f, HN.50t, and LOX-1) in rat plasma. After the plasma proteins were precipitated with methanol containing phenacetin as an internal standard, the analytes were separated on a Luna C18 (2) (5??m, 4.6 × 150?mm)...
  50. Himmelsbach M, Haunschmidt M, Buchberger W, Klampfl C. Microemulsion electrokinetic chromatography with on-line atmospheric pressure photoionization mass spectrometric detection. Anal Chem. 2007;79:1564-8 pubmed
    ..Thereby, limits of detection ranging between 0.5 (carbamazepine) and 5 microg mL(-1) (phenacetin) could be obtained.
  51. Bussy U, Giraudeau P, Silvestre V, Jaunet Lahary T, Ferchaud Roucher V, Krempf M, et al. In situ NMR spectroelectrochemistry for the structure elucidation of unstable intermediate metabolites. Anal Bioanal Chem. 2013;405:5817-24 pubmed publisher
    ..spectra recorded in situ permitted us (1) to elucidate the reaction pathway of the electrochemical oxidation of phenacetin and (2) to reveal the quinone imine as a reactive intermediate species without using any trapping reaction...
  52. Thieler H, Schafer W. [The diagnosis of analgesic nephropathy]. Z Gesamte Inn Med. 1988;43:499-504 pubmed
    ..Finally, the reasons are given for the importance of the exact diagnosis analgesic nephropathy, even in the stage of nephrocirrhosis...
  53. Tan S, New L, Chan E. Prevention of acetaminophen (APAP)-induced hepatotoxicity by leflunomide via inhibition of APAP biotransformation to N-acetyl-p-benzoquinone imine. Toxicol Lett. 2008;180:174-81 pubmed publisher
    ..We concluded that inhibition of NAPQI formation is not a probable pathway that LEF protects APAP-induced hepatotoxicity in human...