Skip to main content

Polymorphic 2-hydroxylation of desipramine

A population and family study

European Journal of Clinical Pharmacology volume 44, pages 445–450 (1993)Cite this article

Summary

We have studied desipramine hydroxylation capacity, determined as the metabolic ratio of desipramine to 2-hydroxydesipramine in the urine after a single oral dose of 10 mg of desipramine, in 340 Swedish Caucasians, including the members of 45 two-generation families.

Desipramine metabolic ratios were bimodally distributed among 237 unrelated subjects and 8% were poor metabolizers. There was a strong correlation between the metabolic ratios for desipramine and debrisoquine in 337 subjects phenotyped with both drugs and there was no dissociation between their capacities to hydroxylate desipramine and debrisoquine.

Complex segregation analysis in the 45 families gave evidence for a major locus with incomplete recessivity (d=0.14) controlling the 2-hydroxylation of desipramine. Simila results were obtained in segregation analysis for debrisoquine. There was evidence for linkage between the CYP2D6 gene and the gene regulating the hydroxylation of desipramine and debrisoquine.

This study has provided unequivocal evidence that the capacity to 2-hydroxylate desipramine is polymorphic and under similar genetic control to the hydroxylation of debrisoquine.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  1. Price-Evans DA, Mahgoub A, Sloan TP, Idle JR, Smith RL (1980) A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population. J Med Genet 17: 102–105

    Google Scholar 

  2. Steiner E, Bertilsson L, Säwe J, Bertling I, Sjöqvist F (1988) Polymorphic debrisoquine hydroxylation in 757 Swedish subjects. Clin Pharmacol Ther 44: 431–435

    Google Scholar 

  3. Alván G, Bechtel P, Iselius L, Gundert-Remy U (1990) Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol 39: 533–537

    Google Scholar 

  4. Steiner E, Iselius L, Alván G, Lindsten J, Sjöqvist F (1985) A family study of genetic and environmental factors determining polymorphic hydroxylation of debrisoquin. Clin Pharmacol Ther 38: 394–401

    Google Scholar 

  5. Zanger UM, Vilbois F, Hardwick JP, Meyer UA (1988) Absence of hepatic cytochrome P450bufI causes genetically deficient debrisoquine oxidation in man. Biochemistry 27: 5447–5454

    Google Scholar 

  6. Kagimoto M, Heim M, Kagimoto K, Zeugin T, Meyer UA (1990) Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine: Study of the function significance of individual mutations by expression of chimeric genes. J Biol Chem 265: 17209–17214

    Google Scholar 

  7. Hanioka N, Kimura S, Meyer UA, Gonzalez FJ (1990) The human CYP2D locus associated with a common genetic defect in drug oxidation: A G1934→A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3′ splice recognition site. Am J Hum Gen 47: 994–1001

    Google Scholar 

  8. Gaedigk A, Blum M, Meyer UA, Eichelbaum M (1990) Sparteine/debrisoquine polymorphism of drug oxidation: the 11.5 kb allele is the result of a deletion of the IID6 gene on chromosome 22. Naunyn-Schmied Arch Pharmacol 341 (Suppl): Abstract 435

  9. Skoda RC, Gonzalez FJ, Demierre A, Meyer UA (1988) Two mutant alleles of the human cytochrome P450db1 gene (P450IID1) associated with genetically deficient metabolism of debrisoquine and other drugs. Proc Natl Acad Sci USA 85: 5240–5243

    Google Scholar 

  10. Hammer W, Sjöqvist F (1967) Plasma levels of monomethylated tricyclic antidepressants during treatment with imipramine-like compounds. Life Sci 6: 1895–1903

    Google Scholar 

  11. Potter WZ, Bertilsson L, Sjöqvist F (1981) Clinical pharmacokinetics of psychotropic drugs. Fundamental and practical aspects. In: van Praag H, Lader MH, Rafaelsen OJ, Sachar EJ (eds) Handbook of biological psychiatry, part VI. Marcel Dekker, New York, pp 71–134

    Google Scholar 

  12. Bertilsson L, Åberg-Wistedt A (1983) The debrisoquine hydroxylation test predicts steady-state plasma levels of desipramine. Br J Clin Pharmacol 15: 388–390

    Google Scholar 

  13. Spina E, Birgersson C, von Bahr C, Ericsson Ö, Mellström B, Steiner E, Sjöqvist F (1984) Phenotypic consistency in hydroxylation of desmethylimipramine and debrisoquine in healthy subjects and in human liver microsomes. Clin Pharmacol Ther 36: 677–682

    Google Scholar 

  14. Spina E, Steiner E, Ericsson Ö, Sjöqvist F (1987) Hydroxylation of desmethylimipramine: dependence on the debrisoquine hydroxylation phenotype. Clin Pharmacol Ther 41: 314–319

    Google Scholar 

  15. Alván G, Bergström K, BorgÅ O, Iselius L, Pedersen N (1983) Family study of genetic and environmental factors determining the protein binding of propranolol. Eur J Clin Pharmacol 25: 437–441

    Google Scholar 

  16. Lennard MS, Silas JH, Smith AJ, Tucker GT (1977) Determination of debrisoquine and its 4-hydroxy metabolite in biological fluids by gas chromatography with flame-ionization and nitrogen-selective detection. J Chromatogr 133: 161–166

    Google Scholar 

  17. Lalouel JM, Morton NE (1981) Complex segregation analysis with pointers. Hum Hered 31: 312–321

    Google Scholar 

  18. MacLean CJ, Morton NE, Yee S (1984) Combined analysis of segregation, linkage and association under an oligogenic model. Comput Biomed Res 17: 471–480

    Google Scholar 

  19. Broly F, Gaedigk A, Heim M, Eichelbaum M, Morike K, Meyer U (1991) Debrisoquine/sparteine hydroxylation genotype and phenotype: Analysis of common mutations and alleles of CYP2D6 in a European population. DNA and Cell Biol 10: 545–558

    Google Scholar 

  20. MacLean CJ, Morton NE, Elston RC (1976) Skewness in commingled distributions. Biometrics 32: 695–699

    Google Scholar 

  21. Dahl ML, Johansson I, Porsmyr Palmertz M, Ingelman-Sundberg M, Sjöqvist F (1992) Analysis of the CYP2D6 gene in relation to debrisoquin and desipramine hydroxylation in a Swedish population. Clin Pharmacol Ther 51: 12–17

    Google Scholar 

  22. Spina E, Arena A, Pisani F (1987) Urinary desipramine hydroxylation index and steady state plasma concentrations of imipramine and desipramine. Ther Drug Monit 9: 129–133

    Google Scholar 

  23. Sjöqvist F, Hammer W, Ideström C-M, Lind M, Tuck D, Åsberg M (1968) Plasma level of monomethylated tricyclic antidepressants and side-effects in man. Proceedings of the European Society for the Study of Drug Toxicity. Vol IX, Toxicity and side-effects of psychotropic drugs. International Congress Series No 145. Excerpta Medica Foundation, pp 246–257

  24. Heim M, Meyer U (1990) Genotyping of poor metabolizers of debrisoquine by allele-specific PCR amplification. Lancet 336: 529–532

    Google Scholar 

Download references

Author information

Author notes

  1. D. Lee

    Present address: Universidad de Panama, Facultad de Medicina, Departamento de Farmacología, Estafeta Universitaria, Panamá, Rep. de Panamá

Affiliations

  1. Department of Clinical Pharmacology, Karolinska Institute, Huddinge Hospital, Huddinge, Sweden

    M.-L. Dahl, C. Alm, J.-O. Svensson, D. Lee & F. Sjöqvist

  2. Department of Surgery, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden

    L. Iselius

  3. Department of Physiological Chemistry, Karolinska Institute, Stockholm, Sweden

    I. Johansson & M. Ingelman-Sundberg

Authors
  1. M.-L. Dahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. Iselius
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Alm
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J.-O. Svensson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. I. Johansson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. Ingelman-Sundberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. F. Sjöqvist
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Dahl, ML., Iselius, L., Alm, C. et al. Polymorphic 2-hydroxylation of desipramine. Eur J Clin Pharmacol 44, 445–450 (1993). https://doi.org/10.1007/BF00315541

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00315541

Key words

  • Desipramine
  • Genetic polymorphism
  • cytochrome P450
  • debrisoquine
  • drug metabolism