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Clinical Pharmacology in Psychiatry pp 181–191Cite as

Pharmacogenetics of Antidepressants

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Part of the book series: Psychopharmacology Series ((PSYCHOPHARM,volume 7))

Abstract

The metabolism of tricyclic antidepressants is catalysed by the cytochrome P- 450 family of isozymes. The tertiary amines amitriptyline, imipramine and chlorimipramine are all demethylated to active secondary amines. Desmethylimipramine and nortriptyline, on the other hand, are hydroxylated in aromatic and benzylic positions, respectively. The latter involves the formation of two isomers, E and Z, each of which occurs in the R and in the S form. These metabolic changes modify the effects of the drugs on monoaminergic neurons.

This study was supported by a grant from the Swedish Medical Research Council (3902).

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References

  • Alexanderson B ( 1972 a) On interindividual variability in plasma levels of nortriptyline and desmethylimipramine in man: a pharmacokinetic and genetic study. Medical Dissertation, Linköping University, Linköping

    Google Scholar 

  • Alexanderson B (1972 b) Pharmacokinetics of desmethylimipramine and nortriptyline in man after single and oral doses — a crossover study. Eur J Clin Pharmacol 5:7–10

    Google Scholar 

  • Alexanderson B (1973) Prediction of steady-state plasma levels of nortriptyline from single oral dose kinetics: a study in twins. Eur J Clin Pharmacol 6: 44–53

    Article  PubMed  CAS  Google Scholar 

  • Alexanderson B, Price-Evans DA, Sjöqvist F (1969) Steady-state plasma levels of nortriptyline in twins: influence of genetic factors and drug therapy. Br Med J 2: 764–768

    Article  Google Scholar 

  • Åsberg M (1983) On the relationship between plasma concentrations of tricyclic antidepressant drugs and therapeutic response. In: Clayton PJ, Barrett JE (eds) Treatment of depression: old controversies and new approaches. Raven, New York, pp 85–104

    Google Scholar 

  • Åsberg M, Price–Evans D, Sjöqvist F (1971) Genetic control of nortriptyline kinetics in man — a study of relatives of propositi with high plasma concentrations. J Med Genet 8: 129–135

    Article  PubMed  Google Scholar 

  • Balant-Gorgia AE, Schulz P, Dayer P, Balant L, Kubli A, Gertsch C, Garrone G (1982) Role of oxidation polymorphism on blood and urine concentrations of amitriptyline and its metabolites in man. Arch Psychiatr Nervenkr 232: 215–222

    Article  PubMed  CAS  Google Scholar 

  • Bertilsson L, Mellström B, Sjöqvist F, Mårtenson B, Åsberg M (1981) Slow hydroxylation of nortriptyline and concomitant poor debrisoquine hydroxylation: clinical implications. Lancet 1: 560–561

    Article  PubMed  CAS  Google Scholar 

  • Bertilsson L, Åsberg-Wistedt A, Gustafsson LL, Nordin C (1985) Extremely rapid hydroxylation of debrisoquine — a case report with implication for treatment with nortriptyline and other tricyclic antidepressants. Ther Drug Monit 7: 242–243

    Article  Google Scholar 

  • Birgersson C, Morgan ET, Jörnvall H, von Bahr C (1986) Purification of a des-methylimipramine and debrisoquine hydroxylation cytochrome P-450 from human liver. Biochem Pharmacol 35: 3165–3166

    Article  PubMed  CAS  Google Scholar 

  • Brøsen K, Gram LF (1988) First-pass metabolism of imipramine and desipramine: impact of the sparteine oxidation phenotype. Clin Pharmacol Ther 43: 400–406

    Article  PubMed  Google Scholar 

  • Brøsen K, Otton V, Gram LF (1986 a) Imipramine demethylation and hydroxylation: impact of the sparteine oxidation phenotype. Clin Pharmacol Ther 40: 543–549

    Google Scholar 

  • Brøsen K, Klysner R, Gram LF, Otton SV, Bech P, Bertilsson L (1986 b) Steady-state concentrations of imipramine and its metabolites in relation to the sparteine/debrisoquine polymorphism. Eur J Clin Pharmacol 30: 679–684

    Google Scholar 

  • Eichelbaum M, Spannbrucker N, Steinke B, Dengler HJ (1979) Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol 16: 183–187

    Article  PubMed  CAS  Google Scholar 

  • Evans DAP, Mahgoub A, Sloan TP, Idle JR, Smith RL (1980) A family and population study at the genetic polymorphism of debrisoquine in white British population. J Med Genet 17: 102–105

    Article  PubMed  CAS  Google Scholar 

  • Gram LF (1977) Plasma level monitoring of tricyclic antidepressant therapy. Clin Pharmacokinet 2: 237–251

    Article  PubMed  CAS  Google Scholar 

  • Gram LF, Kragh-Sørensen P, Kristensen CB, Møller M, Pedersen OL, Thayssen P (1984) Plasma level monitoring of antidepressants: theoretical basis and clinical applications. In: Usdin E, Åsberg M, Bertilsson L, Sjöqvist F (eds) Frontiers in biochemical and pharmacological research in depression. Advances in psychopharmacology. Raven, New York, pp 399–411

    Google Scholar 

  • Gut J, Catin T, Dayer P, Kronbach T, Zanger U, Meyer UA (1986) Debrisoquine/sparteine-type polymorphism of drug oxidation. J Biol Chem 261: 11734–11743

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Hammer W, Martens S, Sjöqvist F (1969) Comparative studies of the metabolism of des-methylimipramine, nortriptyline, and oxyphenylbutazone in man. Clin Pharmacol Ther 10: 44–49

    PubMed  CAS  Google Scholar 

  • Mahgoub A, Idle JR, Dring LG, Lancaster R, Smith RL (1977) Polymorphic hydroxylation of debrisoquine in man. Lancet 2: 584–586

    Article  PubMed  CAS  Google Scholar 

  • Mellström B, Bertilsson L, Säwe J, Schulz H-U, Sjöqvist F (1981) E- and Z-hydroxylation of nortriptyline — relationship to polymorphic debrisoquine hydroxylation. Clin Pharmacol Ther 30: 189–193

    Article  PubMed  Google Scholar 

  • Mellström B, Säwe J, Bertilsson L, Sjöqvist F (1983) Metabolism of amitriptyline — relationship to polymorphic debrisoquine hydroxylation. Clin Pharmacol Ther 24: 516–520

    Article  Google Scholar 

  • Mellström B, Säwe J, Bertilsson L, Sjöqvist F (1985) Amitriptyline metabolism: relation with debrisoquine hydroxylation in nonsmokers. Clin Pharmacol Ther 39: 369–371

    Article  Google Scholar 

  • Perry PJ, Pfohl BM, Holstad SG (1987) The relationship between antidepressant response and tricyclic antidepressant plasma concentrations. A retrospective analysis of the literature using logistic regression analysis. Clin Pharmacokinet 13: 381–392

    Google Scholar 

  • Sjöqvist F, Bertilsson L (1984) Clinical pharmacology of antidepressant drugs. In: Usdin E, Asberg M, Bertilsson L, Sjöqvist F (eds) Frontiers in biochemical and pharmacological research in depression. Advances in biochemical psychopharmacology. Raven, New York, pp 359–372

    Google Scholar 

  • Sjöqvist F, Bertilsson L (1986) Slow hydroxylation of tricyclic antidepressants — relationship to polymorphic drug oxidation. In: Kalow W (ed) Ethnic differences in reactions to drugs and xenobiotics. Liss, New York, pp 169–188

    Google Scholar 

  • Sjöqvist F, Bertilsson L, Asberg M (1980) Monitoring tricyclic antidepressants. Ther Drug Monit 25: 85–93

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Google Scholar 

  • Spina E, Steiner E, Ericsson Ö, Sjöqvist F (1987 b) Hydroxylation of desmethylimipramine: dependence on the debrisoquine hydroxylation phenotype. Clin Pharmacol Ther 41: 457–461

    Google Scholar 

  • Steiner E (1987) Polymorphic debrisoquine hydroxylation. Thesis, Karolinska Institute, Stockholm

    Google Scholar 

  • Steiner E, Spina E (1987) Differences in the inhibitory effect of Cimetidine on desipramine metabolism between rapid and slow debrisoquine hydroxylators. Clin Pharmacol Ther 42: 272–282

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Google Scholar 

  • Steiner E, Dumont E, Spina E, Dahlqvist R (1988 b) Inhibition of desipramine 2- hydroxylations by qninidine and quinine in rapid and slow hydroxylators. Clin Pharmacol Ther 43: 577–581

    Google Scholar 

  • Von Bahr C, Birgersson C, Bertilsson L, Göransson M, Mellström B, Nilsell K, Sjöqvist F (1982) Drug metabolism in human liver microsomes: towards marker substrates for different enzymes. Br J Clin Pharmacol 14: 603P–604 P

    Google Scholar 

  • Von Bahr C, Spina E, Birgersson C, Ericsson Ö, Göransson M, Henthorn T, Sjöqvist F (1985) Inhibition of desmethylimipramine 2-hydroxylation by drugs in human liver microsomes. Biochem Pharmacol 34: 2501–2505

    Article  Google Scholar 

  • Woolhouse N, Adjepon-Yamoah KK, Mellström B, Hedman A, Bertilsson L, Sjöqvist F (1984) Nortriptyline and debrisoquine hydroxylations in Ghanaian and Swedish subjects. Clin Pharmacol Ther 36: 374–378

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology of the Karolinska Institute, Huddinge University Hospital, 141 86, Huddinge, Sweden

    F. Sjöqvist

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  1. F. Sjöqvist
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Editors and Affiliations

  1. Department of Pharmacology, Institute of Medical Biology, University of Tromsø School of Medicine, 9001, Tromsø, Norway

    Svein G. Dahl (Professor of Pharmacology) (Professor of Pharmacology)

  2. Department of Clinical Pharmacology, School of Medicine, Odense University, 5000, Odense C, Denmark

    Lars F. Gram (Professor of Clinical Pharmacology) (Professor of Clinical Pharmacology)

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© 1989 Springer-Verlag Berlin Heidelberg

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Sjöqvist, F. (1989). Pharmacogenetics of Antidepressants. In: Dahl, S.G., Gram, L.F. (eds) Clinical Pharmacology in Psychiatry. Psychopharmacology Series, vol 7. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-74430-3_19

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  • DOI: https://doi.org/10.1007/978-3-642-74430-3_19

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-74432-7

  • Online ISBN: 978-3-642-74430-3

  • eBook Packages: Springer Book Archive

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