Skip to main content
NCBI home page
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1989 Sep;28(3):297–304. doi: 10.1111/j.1365-2125.1989.tb05430.x

Effect of liver disease on dextromethorphan oxidation capacity and phenotype: a study in 107 patients.

D Larrey 1, G Babany 1, M Tinel 1, E Freneaux 1, G Amouyal 1, F Habersetzer 1, P Letteron 1, D Pessayre 1
PMCID: PMC1379948  PMID: 2789923

Abstract

1. The O-demethylation of dextromethorphan to dextrorphan exhibits a genetically-controlled polymorphism, co-segregating with that of debrisoquine hydroxylation. Dextromethorphan has been proposed as a test compound to assess drug oxidation polymorphism. 2. We studied the effects of liver disease of varying severity on dextromethorphan oxidation capacity. Phenotyping was performed using the urinary dextromethorphan/dextrorphan metabolic ratio after oral administration of 40 mg dextromethorphan hydrobromide in 56 patients with cirrhosis and in 51 patients with moderately severe liver disease. 3. Dextromethorphan oxidation capacity was impaired in cirrhotic patients and, to lesser extent, in non cirrhotic patients, as compared with 103 control subjects. 4. The impairment in dextromethorphan oxidation induced by liver disease, was however, much less than that caused by the genetic deficiency. As a result, the prevalence of the poor metabolizer phenotype remained in the same range in patients with cirrhosis (1.8%) and with moderately severe disease (2.0%) as in controls (3.9%). 5. This observation shows that, although liver disease causes some impairment of dextromethorphan O-demethylation, this impairment is not sufficient to modify the assignment of phenotypes.

Full text

PDF
297

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Distlerath L. M., Reilly P. E., Martin M. V., Davis G. G., Wilkinson G. R., Guengerich F. P. Purification and characterization of the human liver cytochromes P-450 involved in debrisoquine 4-hydroxylation and phenacetin O-deethylation, two prototypes for genetic polymorphism in oxidative drug metabolism. J Biol Chem. 1985 Jul 25;260(15):9057–9067. [PubMed] [Google Scholar]
  2. Gonzalez F. J., Skoda R. C., Kimura S., Umeno M., Zanger U. M., Nebert D. W., Gelboin H. V., Hardwick J. P., Meyer U. A. Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature. 1988 Feb 4;331(6155):442–446. doi: 10.1038/331442a0. [DOI] [PubMed] [Google Scholar]
  3. Gut J., Catin T., Dayer P., Kronbach T., Zanger U., Meyer U. A. Debrisoquine/sparteine-type polymorphism of drug oxidation. Purification and characterization of two functionally different human liver cytochrome P-450 isozymes involved in impaired hydroxylation of the prototype substrate bufuralol. J Biol Chem. 1986 Sep 5;261(25):11734–11743. [PubMed] [Google Scholar]
  4. Gut J., Gasser R., Dayer P., Kronbach T., Catin T., Meyer U. A. Debrisoquine-type polymorphism of drug oxidation: purification from human liver of a cytochrome P450 isozyme with high activity for bufuralol hydroxylation. FEBS Lett. 1984 Aug 6;173(2):287–290. doi: 10.1016/0014-5793(84)80792-9. [DOI] [PubMed] [Google Scholar]
  5. Jacqz E., Hall S. D., Branch R. A. Genetically determined polymorphisms in drug oxidation. Hepatology. 1986 Sep-Oct;6(5):1020–1032. doi: 10.1002/hep.1840060534. [DOI] [PubMed] [Google Scholar]
  6. Kahn G. C., Boobis A. R., Murray S., Brodie M. J., Davies D. S. Assay and characterisation of debrisoquine 4-hydroxylase activity of microsomal fractions of human liver. Br J Clin Pharmacol. 1982 May;13(5):637–645. doi: 10.1111/j.1365-2125.1982.tb01430.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Küpfer A., Preisig R. Inherited defects of hepatic drug metabolism. Semin Liver Dis. 1983 Nov;3(4):341–354. doi: 10.1055/s-2008-1040786. [DOI] [PubMed] [Google Scholar]
  8. Lanthier P. L., Reshef R., Shah R. R., Oates N. S., Smith R. L., Morgan M. Y. Oxidation phenotyping in alcoholics with liver disease of varying severity. Alcohol Clin Exp Res. 1984 Sep-Oct;8(5):435–441. doi: 10.1111/j.1530-0277.1984.tb05697.x. [DOI] [PubMed] [Google Scholar]
  9. Larrey D., Amouyal G., Tinel M., Letteron P., Berson A., Labbe G., Pessayre D. Polymorphism of dextromethorphan oxidation in a French population. Br J Clin Pharmacol. 1987 Nov;24(5):676–679. doi: 10.1111/j.1365-2125.1987.tb03230.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Larrey D., Branch R. A. Clearance by the liver: current concepts in understanding the hepatic disposition of drugs. Semin Liver Dis. 1983 Nov;3(4):285–297. doi: 10.1055/s-2008-1040781. [DOI] [PubMed] [Google Scholar]
  11. Larrey D., Distlerath L. M., Dannan G. A., Wilkinson G. R., Guengerich F. P. Purification and characterization of the rat liver microsomal cytochrome P-450 involved in the 4-hydroxylation of debrisoquine, a prototype for genetic variation in oxidative drug metabolism. Biochemistry. 1984 Jun 5;23(12):2787–2795. doi: 10.1021/bi00307a039. [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. Schmid B., Bircher J., Preisig R., Küpfer A. Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation. Clin Pharmacol Ther. 1985 Dec;38(6):618–624. doi: 10.1038/clpt.1985.235. [DOI] [PubMed] [Google Scholar]
  14. Teunissen M. W., Spoelstra P., Koch C. W., Weeda B., van Duyn W., Janssens A. R., Breimer D. D. Antipyrine clearance and metabolite formation in patients with alcoholic cirrhosis. Br J Clin Pharmacol. 1984 Nov;18(5):707–715. doi: 10.1111/j.1365-2125.1984.tb02533.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Vesell E. S. The antipyrine test in clinical pharmacology: conceptions and misconceptions. Clin Pharmacol Ther. 1979 Sep;26(3):275–286. doi: 10.1002/cpt1979263275. [DOI] [PubMed] [Google Scholar]
  16. Zanger U. M., Vilbois F., Hardwick J. P., Meyer U. A. Absence of hepatic cytochrome P450bufI causes genetically deficient debrisoquine oxidation in man. Biochemistry. 1988 Jul 26;27(15):5447–5454. doi: 10.1021/bi00415a010. [DOI] [PubMed] [Google Scholar]
  17. Zoulek G., Roggendorf M., Deinhardt F. Immune response to single dose, multisite, intradermal and to intramuscular administration of vaccine against tick-borne encephalitis virus. Lancet. 1984 Sep 8;2(8402):584–584. doi: 10.1016/s0140-6736(84)90809-2. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society

RESOURCES