Advertisement

Adverse Drug Reaction Reporting and Retrospective Phenotyping for Oxidation Polymorphism

  • David W. J. Clark
  • I. Ralph Edwards
Adverse Drug Experience Report

Summary

A genetically determined impairment in the ability to oxidise sparteine and debriso-quine also affects the oxidation of several other drugs. This impairment in oxidation may result in accumulation of the associated drugs and in an increased susceptibility to adverse reactions from these drugs.

Dunedin houses the New Zealand national centre for the collation and study of adverse drug reactions. Included among the reporting schemes is an intensified monitoring system for newly released drugs, in which physicians report all clinical events occurring during treatment with the drugs under surveillance. The centre thus has available extensive records of names and addresses of prescribes and patients who have been reported as experiencing an adverse event while receiving drug therapy.

We investigated the association between genetically poor oxidation of sparteine and adverse reactions to drugs selected as possibly sharing the sparteine/debrisoquine oxidation pathway; these included perhexiline, metoprolol, debrisoquine, piroxicam, mianserin and nifedipine. A kit containing instructions, a sparteine capsule and a container for urine collection was sent to physicians who reported adverse reactions or events to one of the above drugs for forwarding to the patient.

It appeared possible, after assays of returned urine for sparteine and its metabolites, that adverse reactions to nifedipine were associated with genetically poor oxidation. However, a retrospective study in which sparteine metabolic ratios of 11 patients who had been withdrawn from nifedipine because of adverse reactions were compared with those of 37 patients who had continued on nifedipine without adverse effects did not confirm that adverse reactions to nifedipine were more common among genetically poor oxidisers of sparteine.

Further prospective investigations involving the selected drugs are required to determine whether phenotyping for sparteine oxidation status will assist clinicians in predicting susceptibility to adverse reactions. The study demonstrated that pharmacogenetic, or other, investigations of factors associated with adverse drug reactions can be readily carried out in the general population.

Keywords

Adverse Reaction Nifedipine Metoprolol Piroxicam Poor Metabolisers 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bertilsson L, Aberg-Wistedt A. The debrisoquine hydroxylation test predicts steady-state plasma levels of desipramine. British Journal of Clinical Pharmacology 15: 388–390, 1983CrossRefPubMedGoogle Scholar
  2. Bertilsson L, Eichelbaum M, Mellstrom B, Sawe J, Schulz H-U, et al. Nortriptyline and antipyrine clearance in relation to debrisoquine hydroxylation in man. Life Sciences 27: 1672–1677, 1980.CrossRefGoogle Scholar
  3. Clark DWJ. Genetically determined variability in acetylation and oxidation: therapeutic implications. Drugs 29: 342–375, 1985CrossRefPubMedGoogle Scholar
  4. Clark DWJ, Morgan A, Waal-Manning H. Adverse effects from metoprolol are not generally associated with oxidation status. British Journal of Clinical Pharmacology 18: 965–967, 1984CrossRefPubMedGoogle Scholar
  5. Eichelbaum M, Bertilsson L, Sawe J, Zekorn C. Polymorphic oxidation of sparteine and debrisoquine: related pharmacoge-netic entities. Clinical Pharmacology and Therapeutics 31: 184–186, 1982CrossRefPubMedGoogle Scholar
  6. Eichelbaum M, Reetz K-P, Schmidt EK, Zekorn C. The genetic polymorphism of sparteine metabolism. Xenobiotica 16: 465–481, 1986CrossRefPubMedGoogle Scholar
  7. Eichelbaum M, Spannbrucker N, Steincke B, Dengler HJ. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. European Journal of Clinical Pharmacology 16: 183–187, 1979CrossRefPubMedGoogle Scholar
  8. Idle JR, Mahgoub A, Lancaster R, Smith RL. Hypotensive response to debrisoquine and hydroxylation phenotype. Life Sciences 22: 979–984, 1978CrossRefPubMedGoogle Scholar
  9. Idle JR, Sever PS. Treatment of angina pectoris with nifedipine. British Medical Journal 286: 1978, 1983CrossRefPubMedGoogle Scholar
  10. Inaba T, Otton SV, Kalow W. Deficient metabolism of debrisoquine and sparteine. Clinical Pharmacology and Therapeutics 27: 547–549, 1980CrossRefPubMedGoogle Scholar
  11. Inaba T, Vinks A, Otton SW, Kalow W. Comparative pharma-cogenetics of sparteine and debrisoquine. Clinical Pharmacology and Therapeutics 33: 394–399, 1983CrossRefPubMedGoogle Scholar
  12. Kleinbloesem CH, van Brummelen P, Faber H, Danhof M, Vermeulen NPE, et al. Variability in nifedipine pharmacokinetics and dynamics: a new oxidation polymorphism in man. Biochemical Pharmacology 33: 3721–3724, 1984CrossRefPubMedGoogle Scholar
  13. Lennard MS, Silas JH, Freestone S, Ramsey LE, Tucker GT, et al. Oxidation phenotype: a major determinant of metoprolol metabolism and response. New England Journal of Medicine 307: 1558–1560, 1982CrossRefPubMedGoogle Scholar
  14. Lewis RV, Jackson PR, Ramsey LE. Pharmacokinetics and phar-macodynamics of nifedipine and debrisoquine oxidation phenotype. British Journal of Pharmacology 19: 562P, 1984Google Scholar
  15. Price-Evans DA, Harmer D, Downham DY, Whibley EJ, Idle JR, et al. The genetic control of sparteine and debrisoquine metabolism in man with new methods of analysing bimodal distributions. Journal of Medical Genetics 20: 321–329, 1983CrossRefGoogle Scholar
  16. Shah RR, Oates NS, Idle JR, Smith RL, Lockhart JDF. Impaired oxidation of debrisoquine in patients with perhexiline neuropathy. British Medical Journal 284: 295–299, 1982CrossRefPubMedGoogle Scholar

Copyright information

© ADIS Press Limited 1988

Authors and Affiliations

  • David W. J. Clark
    • 1
  • I. Ralph Edwards
    • 1
  1. 1.Department of Pharmacology and National Toxicology GroupUniversity of Otago Medical SchoolDunedinNew Zealand

Personalised recommendations