Advertisement

European Journal of Clinical Pharmacology

, Volume 43, Issue 4, pp 405–411 | Cite as

Steady-state plasma levels of clomipramine and its metabolites: Impact of the sparteine/debrisoquine oxidation polymorphism

  • K. Kramer Nielsen
  • K. Brøsen
  • L. F. Gram
  • Danish University Antidepressant Group
Originals

Summary

After an initial placebo week, 37 depressed in-patients were treated with the fixed dose of 75 mg clomipramine b. d. A sparteine test was carried out during the placebo period and again during the second week of active therapy. Blood for drug assay was collected at the end of the inter-dose interval in the (morning) at weekly intervals. Clomipramine and four metabolites (desmethylclomipramine, didesmethylclomipramine, 8-hydroxyclomipramine, and 8-hydroxydesmethylclomipramine) in plasma were assayed by reversed phase HPLC. The clomipramine and desmethylclomipramine steady-state plasma levels varied by factors of 11 and 9, respectively, and the clomipramine/8-hydroxyclomipramine and desmethylclomipramine/8-hydroxydesmethylclomipramine ratios both varied by 7-fold.

During the placebo week, 36 patients were phenotyped as extensive metabolizers (EM) (metabolic ratio, MR, 0.1–2.0), and one patient was phenotyped as a poor metabolizer (PM) (MR > 300). During clomipramine treatment, one patient changed phenotype from EM to PM (MR = 140). In the EM, the median of the MR increased from 0.4 to 2.3. There was a statistically significant correlation between the MR before and during clomipramine treatment, even when the PM was excluded.

Neither the steady-state plasma clomipramine levels nor the clomipramine/desmethylclomipramine ratios showed a significant correlation with the MR. In contrast, the desmethylclomipramine and didesmethylclomipramine steady-state levels and the desmethylclomIpramine/8-hydroxydesmethylclomipramine and clomipramine/8-hydroxyclomipramine ratios showed a significant positive correlation with the MR. The PM had the highest steady-state plasma desmethylclomipramine level and the highest desmethylclomipramine/8-hydroxydesmethylclomipramine ratio. These correlation coefficients (rs) were generally increased when the correlation analyses were based on the MR obtained during clomipramine treatment.

The results suggest that the 8-hydroxylation of clomipramine and of desmethylclomipramine are catalyzed by the same isozyme that oxidises sparteine, CYP2D6. The N-demethylation of clomipramine appears to be less clearly related to the activity of CYP2D6. Clomipramine appeared to cause more potent inhibition of sparteine oxidation than that seen previously with other tricyclic antidepressants.

Key words

Clomipramine, Sparteine genetic polymorphism, drug oxidation, metabolic pathway, interaction, P450 isozyme 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Balant-Gorgia AE, Balant LP, Genet Ch, Dayer P, Aeschlimann JM, Garrone G (1986) Importance of oxidative polymorphism and levomepromazine treatment on the steady-state blood concentration of clomipramine and its major metabolites. Eur J Clin Pharmacol 31: 449–455PubMedGoogle Scholar
  2. Balant-Gorgia AE, Schulz P, Dayer P, Balant L, Kubli A, Hertsch C, Garrone G (1982) Role of oxidation polymorphism on blood and urine concentrations of amitriptyline and its metabolites in man. Arch Psych Neurol Sci 232: 215–222Google Scholar
  3. Bertilsson L, Åberg-Wistedt A (1983) The debrisoquine hydroxylation test predicts steady-state plasma levels of desipramine. Br J Clin Pharmacol 15: 388–390PubMedGoogle Scholar
  4. Brøsen K (1990) Recent developments in hepatic drug oxidation: implications for clinical pharmacokinetics. Clin Pharmacokinet 18: 220–239PubMedGoogle Scholar
  5. Brøsen K, Gram LF (1988) First-pass metabolism of imipramine and desipramine: impact of the sparteine oxidation phenotype. Clin Pharmacol Ther 43: 400–406PubMedGoogle Scholar
  6. Brøsen K, Gram LF (1989) Clinical significance of the sparteine/debrisoquine oxidation polymorphism. Eur J Clin Pharmacol 36: 537–547PubMedGoogle Scholar
  7. Brøsen K, Klysner R, Gram LF, Otton SV, Bech P, Bertilsson L (1986a) Steady-state concentrations of imipramine and its metabolites in relation to the sparteine/debrisoquine polymorphism. Eur J Clin Pharmacol 30: 679–684PubMedGoogle Scholar
  8. Brøsen K, Otton SV, Gram LF (1985) Sparteine oxidation polymorphism in Denmark. Acta Pharmacol Toxicol 57: 357–360Google Scholar
  9. Brøsen K, Otton SV, Gram LF (1986b) Imipramine demethylation and hydroxylation: impact of the sparteine oxidation phenotype. Clin Pharmacol Ther 40: 543–549PubMedGoogle Scholar
  10. Brøsen K, Zeugin T, Meyer UA (1991) Role of P450IID6, the target of the sparteine/debrisoquine oxidation polymorphism, in the metabolism of imipramine. Clin Pharmacol Ther 49: 609–617PubMedGoogle Scholar
  11. Ciraulo DA, Barnhill J, Boxenbaum H (1985) Pharmacokinetic interaction of disulfiram and antidepressants. Clin Res Rep 142: 1373–1374Google Scholar
  12. Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE (1991) The effect of paroxetine and other specific serotonin re-uptake inhibitors on cytochrome P450IID6 activity in human liver microsomes. Br J Clin Pharmacol 32: 658P-659PGoogle Scholar
  13. Danish University Antidepressant Group (1986) Citalopram: clinical effect profile in comparison with clomipramine. A controlled multicenter study. Psychopharmacology 90: 131–138Google Scholar
  14. Danish University Antidepressant Group (1990) Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. J Affective Disord 18: 289–299Google Scholar
  15. Eichelbaum M, Bertilsson L, Säwe J, Zekorn C (1982) Polymorphic oxidation of sparteine and debrisoquine: related pharmacogenetic entities. Clin Pharmacol Ther 32: 184–186Google Scholar
  16. Eichelbaum M, Spannbrucker N, Steincke B, Dengler HJ (1979) Defective N-oxidation of sparteine in man: A new pharmacogenetic defect. Eur J Clin Pharmacol 16: 183–187PubMedGoogle Scholar
  17. Evans DAP, 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: 102–105PubMedGoogle Scholar
  18. Gram LF (1977) Plasma level monitoring of tricyclic antidepressant therapy. Clin Pharmacokinet 2: 237–251PubMedGoogle Scholar
  19. Gram LF, Bech P, Reisby N, Sylvester Jørgensen O (1981) Methodology in studies on plasma level/effect relationship of tricyclic antidepressants. In: Usdin E. (ed) Clinical Pharmacology in Psychiatry. Elsevier, New York, pp 155–171Google Scholar
  20. Gram LF, Brosen K, Kragh-Sørensen P, Christensen P (1989) Steady-state plasma levels of E- and Z-10-OH-nortriptyline in nortriptyline-treated patients: Significance of concurrent medication and the sparteine oxidation phenotype. Ther Drug Monit 11: 508–514PubMedGoogle Scholar
  21. Gram LF, Kragh-Sørensen P, Bech P, Reisby N, Vestergaard P, Bolwig TG (1989) Danish University Antidepressant Group (DUAG) — A permanent independent multicenter group for improved quality in clinical testing of new antidepressants. Eur J Clin Pharmacol 36 [suppl.]: A157Google Scholar
  22. Gut J, Gasser R, Dayer P, Kronbach T, Catin T, Meyer UA (1984) Debrisoquine-type polymorphism of drug oxidation: purification from human liver of a cytochrome P450 isozyme with high activity for bufuralol hydroxylation. FEBS 173: 287–290Google Scholar
  23. Mellström B, Bertilsson L, Träskman L, Rollins D, Åsberg M, Sjöqvist (1979) Intraindividual similarity in the metabolism of amitriptyline and clomipramine in depressed patients. Pharmacology 19: 282–287PubMedGoogle Scholar
  24. Mellström B, Bertilsson L, Lou Y-C, Säwe J, Sjöqvist F (1983) Amitriptyline metabolism: relationship to polymorphic debrisoquine hydroxylation. Clin Pharmacol Ther 34: 516–520PubMedGoogle Scholar
  25. Mellström B, Bertilsson L, Säwe J, Schulz HU, Sjöqvist F (1981) E- and Z-10-hydroxylation of nortriptyline: relationship to polymorphic debrisoquine hydroxylation. Clin Pharmacol Ther 30: 189–193PubMedGoogle Scholar
  26. Mellström B, Säwe J, Bertilsson L, Sjögvist F (1986) Amitriptyline metabolism: association with debrisoquine hydroxylation in nonsmokers. Clin Pharmacol Ther 39: 369–371PubMedGoogle Scholar
  27. Nebert DW, Nelson DR, Coon MJ, Estabrook RW, Feyereisen R, Fuji-Kuriyama Y, Gonzales FJ, Guengerich FP, Gunsalus IC, Johnson EF, Loper JC, Sato R, Waterman MR, Waxman DJ (1991) The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature. DNA Cell Biol M. 10: 1–14Google Scholar
  28. Otton SV, Inaba T, Kalow W (1983) Inhibition of sparteine oxidation in human liver by tricyclic antidepressants and other drugs. Life Sci 32: 795–800PubMedGoogle Scholar
  29. Reisby N, Gram LF, Bech P, Sihm F, Krautwald O, Elley J, Ortmann J, Christiansen J (1979) Clomipramine: plasma levels and clinical effects. Psychopharmacology 3: 341–351Google Scholar
  30. Sindrup SH, Gram LF, Skjold T, Grodum E, Brosen K, Beck-Nielsen H (1990) Clomipramine vs desipramine vs placebo in the treatment of diabetic neuropathy symptoms. A double-blind crossover study. Br J Clin Pharmacol 30: 683–691PubMedGoogle Scholar
  31. Skjelbo E, Brosen K (1992) Inhibitors of imipramine metabolism by human liver microsomes. Br J Clin Pharmacol (in press)Google Scholar
  32. Skjelbo E, Brøsen K, Hallas J, Gram LF (1991) The mephenytoin oxidation polymorphism is partially responsible for the N-demethylation of imipramine. Clin Pharmacol Ther 49: 18–23PubMedGoogle Scholar
  33. Spina E, Birgersson C, von Bahr C, Ericsson Ö, Mellström B, Steiner E, Sjögvist F (1984) Phenotypic consistency in hydroxylation of desmethylclomipramine and debrisoquine in healthy subjects and in human liver microsomes. Clin Pharmacol Ther 36: 677–682PubMedGoogle Scholar
  34. Syvählahti EKG, Lindberg R, Kallio J, de Vocht M (1986) Inhibitory effects of neuroleptics on debrisoquine oxidation in man. Br J Clin Pharmacol 22: 89–92PubMedGoogle Scholar
  35. Träskman L, Åsberg M, Bertilsson L, Cronholm B, Mellström B, Neckers LM, Sjögvist F, Thorén P, Tybring G (1979) Plasma levels of clomipramine and its demethyl metabolites during treatment of depression. Clin Pharmacol Ther 26: 600–610PubMedGoogle Scholar
  36. Vandel B, Vandel S, Jounet JM, Allers G, Volmat R (1982) Relationship between the plasma concentration of clomipramine and desmethylclomipramine in depressive patients and the clinical response. Eur J Clin Pharmacol 22: 15–20PubMedGoogle Scholar
  37. Vinks A, Inaba T, Otton SV, Kalow W (1982) Sparteine metabolism in Canadien Caucasians. Clin Pharmacol Ther 31: 23–29PubMedGoogle Scholar
  38. Woolhouse NM, Adjepon-Yamoah KK, Mellström B, Hedman A, Bertilsson L, Sjöqvist F (1984) Nortriptyline and debrisoquine hydroxylation in Ghanaian and Swedish subjects. Clin Pharmacol Ther 36: 374–378PubMedGoogle Scholar
  39. Zanger UM, Vilbois F, Hardwick J, Meyer UA (1988) Absence of hepatic cytochrome P450bufl causes genetically deficient debrisoguine oxidation in man. Biochemistry 27: 5447–5454PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • K. Kramer Nielsen
    • 1
  • K. Brøsen
    • 1
  • L. F. Gram
    • 1
  • Danish University Antidepressant Group
    • 1
  1. 1.Department of Clinical Pharmacology, Institute of Medical BiologyOdense UniversityOdenseDenmark

Personalised recommendations