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. 1983 Aug;16(2):157–166. doi: 10.1111/j.1365-2125.1983.tb04980.x

The contribution of genetically determined oxidation status to inter-individual variation in phenacetin disposition.

H W Devonshire, I Kong, M Cooper, T P Sloan, J R Idle, R L Smith
PMCID: PMC1427984  PMID: 6615690

Abstract

The oxidative O-de-ethylation and aromatic 2-hydroxylation of phenacetin have been investigated in panels of extensive (EM, n = 13) and poor (PM, n = 10) metabolizers of debrisoquine. The EM group excreted in the urine significantly more paracetamol (EM: 40.8 +/- 14.9% dose/0-8 h; PM: 29.2 +/- 8.7% dose/0-8 h, 2P less than 0.05) and significantly less 2-hydroxylated metabolites (EM: 4.7 +/- 2.3% dose/0-8 h; PM: 9.7 +/- 3.5% dose/0-8 h, 2P less than 0.005) than the PM group. Apparent first-order rate constants, calculated from pooled phenotype data, for overall elimination of phenacetin (k) and formation of paracetamol (kml) were higher in the EM group (EM: k = 0.191 +/- 0.151 h-1; kml = 0.091 +/- 0.025 h-1; PM: k = 0.098 +/- 0.035 h-1, 2P less than 0.05, kml = 0.052 +/- 0.019 h-1, 2P less than 0.05) than the PM group. The apparent first-order rate constant for 2-hydroxylation displayed no significant inter-phenotype differences. Correlation analysis demonstrated that genetically determined oxidation status accounted for approximately 50% of the inter-individual variability in phenacetin disposition encountered in this study.

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Selected References

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  1. ASK-UPMARK E. Migraine as a deadly disease. Br Med J. 1960 Sep 17;2(5202):823–825. doi: 10.1136/bmj.2.5202.823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. B4uch H., Gerhards W., Pfleger K., Rüdiger W., Rummel W. Metabolische Umwandlung von Phenacetin und N-Acetyl-p-aminophenol nach Vorbehandlung mit Phenobarbital. Biochem Pharmacol. 1967 Aug;16(8):1585–1599. doi: 10.1016/0006-2952(67)90137-2. [DOI] [PubMed] [Google Scholar]
  3. Bertilsson L., Dengler H. J., Eichelbaum M., Schulz H. U. Pharmacogenetic covariation of defective N-oxidation of sparteine and 4-hydroxylation of debrisoquine. Eur J Clin Pharmacol. 1980 Feb;17(2):153–155. doi: 10.1007/BF00562624. [DOI] [PubMed] [Google Scholar]
  4. Büch H., Gerhards W., Karachristianidis G., Pfleger K., Rummel W. Hemmung der durch Phenacetin und p-Phenetidin verursachten Methämoglobin-Bildung durch Barbiturate. Biochem Pharmacol. 1967 Aug;16(8):1575–1583. doi: 10.1016/0006-2952(67)90136-0. [DOI] [PubMed] [Google Scholar]
  5. Conney A. H., Pantuck E. J., Hsiao K. C., Garland W. A., Anderson K. E., Alvares A. P., Kappas A. Enhanced phenacetin metabolism in human subjects fed charcoal-broiled beef. Clin Pharmacol Ther. 1976 Dec;20(6):633–642. doi: 10.1002/cpt1976206633. [DOI] [PubMed] [Google Scholar]
  6. Cummings A. J., King M. L., Martin B. K. A kinetic study of drug elimination: the excretion of paracetamol and its metabolites in man. Br J Pharmacol Chemother. 1967 Feb;29(2):150–157. doi: 10.1111/j.1476-5381.1967.tb01948.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cummings A. J., Martin B. K., Park G. S. Kinetic considerations relating to the accrual and elimination of drug metabolites. Br J Pharmacol Chemother. 1967 Feb;29(2):136–149. doi: 10.1111/j.1476-5381.1967.tb01947.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Davies D. S., Kahn G. C., Murray S., Brodie M. J., Boobis A. R. Evidence for an enzymatic defect in the 4-hydroxylation of debrisoquine by human liver. Br J Clin Pharmacol. 1981 Jan;11(1):89–91. doi: 10.1111/j.1365-2125.1981.tb01108.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Evans D. A., Mahgoub A., Sloan T. P., Idle J. R., Smith R. L. A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population. J Med Genet. 1980 Apr;17(2):102–105. doi: 10.1136/jmg.17.2.102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Jaffé E. R. Oxidative hemolysis, or "what made the red cell break"? N Engl J Med. 1972 Jan 20;286(3):156–157. doi: 10.1056/NEJM197201202860311. [DOI] [PubMed] [Google Scholar]
  11. Kitchen I., Tremblay J., André J., Dring L. G., Idle J. R., Smith R. L., Williams R. T. Interindividual and interspecies variation in the metabolism of the hallucinogen 4-methoxyamphetamine. Xenobiotica. 1979 Jul;9(7):397–404. doi: 10.3109/00498257909038744. [DOI] [PubMed] [Google Scholar]
  12. Mahgoub A., Idle J. R., Dring L. G., Lancaster R., Smith R. L. Polymorphic hydroxylation of Debrisoquine in man. Lancet. 1977 Sep 17;2(8038):584–586. doi: 10.1016/s0140-6736(77)91430-1. [DOI] [PubMed] [Google Scholar]
  13. Martin B. K. Drug urinary excretion data--some aspects concerning the interpretation. Br J Pharmacol Chemother. 1967 Feb;29(2):181–193. doi: 10.1111/j.1476-5381.1967.tb01951.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Murray R. M. Genesis of analgesic nephropathy in the United Kingdom. Kidney Int. 1978 Jan;13(1):50–57. doi: 10.1038/ki.1978.7. [DOI] [PubMed] [Google Scholar]
  15. Nery R. Some new aspects of the metabolism of phenacetin in the rat. Biochem J. 1971 Apr;122(3):317–326. doi: 10.1042/bj1220317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nordenfelt O. Deaths from renal failure in abusers of phenacetin-containing drugs. Acta Med Scand. 1972 Jan-Feb;191(1-2):11–16. [PubMed] [Google Scholar]
  17. POLI M. Néphropathie médicale bilatérale familiale à évolution chronique. Helv Med Acta. 1955 May;22(2):109–122. [PubMed] [Google Scholar]
  18. Pantuck E. J., Hsiao K. C., Loub W. D., Wattenberg L. W., Kuntzman R., Conney A. H. Stimulatory effect of vegetables on intestinal drug metabolism in the rat. J Pharmacol Exp Ther. 1976 Aug;198(2):278–283. [PubMed] [Google Scholar]
  19. Pantuck E. J., Hsiao K. C., Maggio A., Nakamura K., Kuntzman R., Conney A. H. Effect of cigarette smoking on phenacetin metabolism. Clin Pharmacol Ther. 1974 Jan;15(1):9–17. doi: 10.1002/cpt19741519. [DOI] [PubMed] [Google Scholar]
  20. Raaflaub J., Dubach U. C. Dose-dependent change in the pattern of phenacetin metabolism in man and its possible significance in analgesic nephropathy. Klin Wochenschr. 1969 Dec 1;47(23):1286–1287. doi: 10.1007/BF01487561. [DOI] [PubMed] [Google Scholar]
  21. Raaflaub J., Dubach U. C. On the pharmacokinetics of phenacetin in man. Eur J Clin Pharmacol. 1975 Apr 4;8(3-4):261–265. doi: 10.1007/BF00567125. [DOI] [PubMed] [Google Scholar]
  22. Shah R. R., Oates N. S., Idle J. R., Smith R. L. Genetic impairment of phenformin metabolism. Lancet. 1980 May 24;1(8178):1147–1147. doi: 10.1016/s0140-6736(80)91604-9. [DOI] [PubMed] [Google Scholar]
  23. Shahidi N. T., Hemaidan A. Acetophenetidin-induced methemoglobinemia and its relation to the excretion of diazotizable amines. J Lab Clin Med. 1969 Oct;74(4):581–585. [PubMed] [Google Scholar]
  24. Shively C. A., Vesell E. S. Temporal variations in acetaminophen and phenacetin half-life in man. Clin Pharmacol Ther. 1975 Oct;18(4):413–424. doi: 10.1002/cpt1975184413. [DOI] [PubMed] [Google Scholar]
  25. Sloan T. P., Idle J. R., Smith R. L. Influence of DH/DL alleles regulating debrisoquine oxidation on phenytoin hydroxylation. Clin Pharmacol Ther. 1981 Apr;29(4):493–497. doi: 10.1038/clpt.1981.68. [DOI] [PubMed] [Google Scholar]
  26. Sloan T. P., Mahgoub A., Lancaster R., Idle J. R., Smith R. L. Polymorphism of carbon oxidation of drugs and clinical implications. Br Med J. 1978 Sep 2;2(6138):655–657. doi: 10.1136/bmj.2.6138.655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Thomas B. H., Coldwell B. B., Zeitz W., Solomonraj G. Effect of aspirin, caffeine, and codeine on the metabolism of phenacetin and acetaminophen. Clin Pharmacol Ther. 1972 Nov-Dec;13(6):906–910. doi: 10.1002/cpt1972136906. [DOI] [PubMed] [Google Scholar]

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