Skip to main content
NCBI home page
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1982 Aug;14(2):301–303. doi: 10.1111/j.1365-2125.1982.tb01982.x

Defective metabolism of metoprolol in poor hydroxylators of debrisoquine.

M S Lennard, J H Silas, S Freestone, J Trevethick
PMCID: PMC1427748  PMID: 6125207

Abstract

Eight healthy volunteers received oral metoprolol 200 mg once daily for a week. The AUC, half-life and duration of beta-adrenoceptor blockade on day 7 was much greater in two subjects than in the remaining six. This suggested that the metabolism of metoprolol was impaired in two and the effect was therefore prolonged. Subsequent testing of oxidation phenotype with oral debrisoquine showed that the subjects with high metoprolol availability were also poor hydroxylators of debrisoquine. The urinary debrisoquine/4-hydroxydebrisoquine ratio was highly correlated with metoprolol AUC, half-life and beta-adrenoceptor blockade at 24 h. Thus patients with a genetic defect in drug oxidation, when treated with metoprolol, are likely to have high plasma concentrations and a prolonged effect.

Full text

PDF
301

Selected References

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

  1. Alvan G., von Bahr C., Seidemann P., Sjöqvist F. High plasma concentrations of beta-receptor blocking drugs and deficient debrisoquine hydroxylation. Lancet. 1982 Feb 6;1(8267):333–333. doi: 10.1016/s0140-6736(82)91583-5. [DOI] [PubMed] [Google Scholar]
  2. Bertilsson L., Eichelbaum M., Mellström B., Säwe J., Schulz H. U., Sjöqvist F. Nortriptyline and antipyrine clearance in relation to debrisoquine hydroxylation in man. Life Sci. 1980 Nov 3;27(18):1673–1677. doi: 10.1016/0024-3205(80)90642-6. [DOI] [PubMed] [Google Scholar]
  3. Borg K. O., Carlsson E., Hoffmann K. J., Jönsson T. E., Thorin H., Wallin B. Metabolism of metoprolol-(3-h) in man, the dog and the rat. Acta Pharmacol Toxicol (Copenh) 1975;36(Suppl 5):125–135. doi: 10.1111/j.1600-0773.1975.tb03329.x. [DOI] [PubMed] [Google Scholar]
  4. EVANS D. A., WHITE T. A. HUMAN ACETYLATION POLYMORPHISM. J Lab Clin Med. 1964 Mar;63:394–403. [PubMed] [Google Scholar]
  5. 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]
  6. Idle J. R., Sloan T. P., Smith R. L., Wakile L. A. Application of the phenotyped panel approach to the detection of polymorphism of drug oxidation in man [proceedings]. Br J Pharmacol. 1979 Jul;66(3):430P–431P. [PMC free article] [PubMed] [Google Scholar]
  7. Jordö L., Attman P. O., Aurell M., Johansson L., Johnsson G., Regårdh C. G. Pharmacokinetic and pharmacodynamic properties of metoprolol in patients with impaired renal function. Clin Pharmacokinet. 1980 Mar-Apr;5(2):169–180. doi: 10.2165/00003088-198005020-00004. [DOI] [PubMed] [Google Scholar]
  8. Lennard M. S., Silas J. H., Smith A. J., Tucker G. T. Determination of debrisoquine and its 4-hydroxy metabolite in biological fluids by gas chromatography with flame-ionization and nitrogen-selective detection. J Chromatogr. 1977 Mar 11;133(1):161–166. doi: 10.1016/s0021-9673(00)89216-x. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Mbanefo C., Bababunmi E. A., Mahgoub A., Sloan T. P., Idle J. R., Smith R. L. A study of the debrisoquine hydroxylation polymorphism in a Nigerian population. Xenobiotica. 1980 Nov;10(11):811–818. doi: 10.3109/00498258009033811. [DOI] [PubMed] [Google Scholar]
  11. Perry H. M., Jr Late toxicity to hydralazine resembling systemic lupus erythematosus or rheumatoid arthritis. Am J Med. 1973 Jan;54(1):58–72. doi: 10.1016/0002-9343(73)90084-3. [DOI] [PubMed] [Google Scholar]
  12. Regårdh C. G., Johnsson G. Clinical pharmacokinetics of metoprolol. Clin Pharmacokinet. 1980 Nov-Dec;5(6):557–569. doi: 10.2165/00003088-198005060-00004. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Shah R. R., Oates N. S., Idle J. R., Smith R. L., Lockhart J. D. Impaired oxidation of debrisoquine in patients with perhexiline neuropathy. Br Med J (Clin Res Ed) 1982 Jan 30;284(6312):295–299. doi: 10.1136/bmj.284.6312.295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Silas J. H., Lennard M. S., Tucker G. T., Smith A. J., Malcolm S. L., Marten T. R. Why hypertensive patients vary in their response to oral debrisoquine. Br Med J. 1977 Feb 12;1(6058):422–425. doi: 10.1136/bmj.1.6058.422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. 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]
  17. Tucker G. T., Silas J. H., Iyun A. O., Lennard M. S., Smith A. J. Polymorphic hydroxylation of debrisoquine. Lancet. 1977 Oct 1;2(8040):718–718. doi: 10.1016/s0140-6736(77)90527-x. [DOI] [PubMed] [Google Scholar]
  18. von Bahr C., Collste P., Frisk-Holmberg M., Haglund K., Jorfelt L., Orme M., Ostman J., Sjoqvist F. Plasma levels and effects of metoprolol on blood pressure, adrenergic beta receptor blockade, and plasma renin activity in essential hypertension. Clin Pharmacol Ther. 1976 Aug;20(2):130–137. doi: 10.1002/cpt1976202130. [DOI] [PubMed] [Google Scholar]

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

RESOURCES