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Psychotropic Drug Metabolism and Clinical Monitoring

  • A. E. Balant-Gorgia
  • L. P. Balant
Conference paper
Part of the Psychopharmacology Series book series (PSYCHOPHARM, volume 10)

Abstract

The major causes of variability in blood concentrations of psychoactive substances are presystemic and systemic hepatic clearances, with a few exceptions such as lithium or sulpiride. The main reason for this variability is to be found in the lipophilic nature of most psychotropes which favors elimination by metabolism rather than by renal excretion of the unchanged drug. The nature of this variability is, in part, of defined genetic origin (see Brøsen et al., this volume) and, in part, of undefined genetic or poorly controlled environment factors, which interfere with aging, or pathological conditions. Analysis of the interplay of drug metabolism and therapeutic monitoring would thus imply a review of all the aspects of biotransformation which may induce intra- and interindividual variability. Confronted with this (almost) insuperable task, we have decided to concentrate on selected aspects of metabolism. The criteria behind these choices are summarized by three questions: (1) which substances (parent drug and/or metabolite) should be mentioned? (2) how should they be determined? and (3) which approach should be adopted for the interpretation of the concentration data? For each area of interest, we have tried to summarize current knowledge and to express an opinion, which is not necessarily the result of a general consensus.

Keywords

High Pressure Liquid Chromatography Therapeutic Drug Monitoring Clinical Monitoring Fluphenazine Decanoate Plasma Level Monitoring 
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.

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References

  1. Altamura AC, Mauri M, Cavallaro R, Regazzetti MG, Bareggi SR (1989) Hydroxyhaloperidol and clinical outcome in schizophrenia. In: Dahl SG, Gram LF (eds) Clinical pharmacology in psychiatry. Springer Berlin Heidelberg New York, pp 263–268 (Psychopharmacology series 7 )Google Scholar
  2. Axelsson R, Mårtensson E (1983) Clinical effects related to the serum concentrations of thioridazine and its metabolites. In: Gram LF, Usdin E, Dahl SG, Krag-Sørensen P, Sjöqvist F, Morselli PL (eds) Clinical pharmacology in psychiatry. Macmillan, London, pp 165–174Google Scholar
  3. Balant-Gorgia AE, Balant LP (1987) Antipsychotic drugs: Clinical pharmacokinetics of potential candidates for plasma concentration monitoring. Clin Pharmacokinet 13: 65–90PubMedCrossRefGoogle Scholar
  4. Balant-Gorgia AE, Balant LP, Genet C, Dayer P, Aeschlimann JM, Garrone G (1986) Importance of oxidative polymorphism and levomepromazine treatment on the steady-state blood concentrations of clomipramine and its major metabolites. Eur J Clin Pharmacol 31: 449–455PubMedCrossRefGoogle Scholar
  5. Balant-Gorgia AE, Balant LP, Gex-Fabry M, Genet C (1987) Stereoselective disposition of flupentixol: influence on steady-state plasma concentrations in schizophrenic patients. Eur J Drug Metab Pharmacokinet 12: 123–128PubMedCrossRefGoogle Scholar
  6. Balant-Gorgia AE, Balant LP, Garrone G (1989) High blood concentrations of imipramine or clomipramine and therapeutic failure: a case report study using drug monitoring data. Ther Drug Monit 11: 415–420PubMedGoogle Scholar
  7. Bertilsson L, Mellström B, Nordin C, Siwers B, Sjöqvist F (1983) Stereospecific 10- hydroxylation of nortriptyline: genetic aspects and importance for biochemical and clinical effects. In: Gram LF, Usdin E, Dahl SG, Krag-Sørensen P, Sjöqvist F, Morselli PL (eds) Clinical pharmacology in psychiatry. Macmillan, London, pp 217–226Google Scholar
  8. Bertilsson L, Nordin C, Otani K, Resul B, Scheinin M, Siwers B, Sjöqvist F (1986) Disposition of single oral doses of E-10-hydroxynortriptyline in healthy subjects, with some observations on pharmacodynamic effects. Clin Pharmacol Ther 40: 261–267PubMedCrossRefGoogle Scholar
  9. Bertilsson L, Dahl-Puustinen ML, Nordin C (1989) E-10-hydroxynortriptyline: effects and disposition of a potential novel antidepressant. In: Dahl SG, Gram LF (eds) Clinical pharmacology in psychiatry. Springer, Berlin Heidelberg New York, pp 52–59 (Psychopharmacology series 7 )Google Scholar
  10. Bock JL, Giller E, Gray S, Jatlow P (1982) Steady-state plasma concentrations of cis- and trans-10-OH-amitriptyline metabolites. Clin Pharmacol Ther 31: 609–616PubMedCrossRefGoogle Scholar
  11. Broadhurst AD, James HD, Delia Corte L, Heeley AF (1977) Clomipramine plasma level and clinical response. Postgrad Med J 53 Suppl 4: 139–145Google Scholar
  12. Brøsen K, Gram LF, Klysner R, Bech P (1986) Steady-state levels of imipramine and its metabolites: significance of dose-dependent kinetics. Eur J Clin Pharmacol 30: 43–49PubMedCrossRefGoogle Scholar
  13. Browning JL, Harrington CA, Davis CM (1985) Quantification of reduced haloperidol and haloperidol by radioimmunoassay. J Immunoassay 6: 45–66PubMedCrossRefGoogle Scholar
  14. Brunswick DJ, Amsterdam JD, Mendels J, Stern SL (1979) Prediction of steady-state imipramine and desmethylimipramine plasma concentrations from single-dose data. Clin Pharmacol Ther 25: 605–610PubMedGoogle Scholar
  15. Chakraborty BS, Hubbard JW, Hawes EM, McKay G, Cooper JK, Gurnsey T, Korchinsky ED, Midha KK (1989) Interconversion between haloperidol and reduced haloperidol in healthy volunteers. Eur J Clin Pharmacol 37: 45–48PubMedGoogle Scholar
  16. Chang WH, Chen TY, Lee CF, Hu WH, Yeh EK (1987) Low plasma reduced haloperido/haloperidol ratios in Chinese patients. Biol Psychiatry 22: 1406–1408PubMedCrossRefGoogle Scholar
  17. Chang WH, Lin SK, Jann MW (1991) Interconversion between haloperidol and reduced haloperidol in schizophrenic patients and guinea pigs: a steady-state study. J Clin Psychopharmacol 11: 99–105PubMedCrossRefGoogle Scholar
  18. Dahl SG (1981) Active metabolites of phenothiazine drugs. In: Usdin E, Dahl SG, Gram LF, Lingjaerde O (eds) Clinical pharmacology in psychiatry. Macmillan, London, pp 125–137Google Scholar
  19. Dahl SG (1982) Actives metabolites of neuroleptic drugs: possible contribution to therapeutic and toxic effects. In: Raven, New York 4: 33–40Google Scholar
  20. Dahl SG (1986) Plasma level monitoring of antipsychotic drugs clinical utility. Clin Pharmacol 11: 36–61CrossRefGoogle Scholar
  21. Dahl SG (1990) Conditions for meaningful plasma level monitoring of neuroleptics. In: Stefanis CN, Rabavilas AD, Soldatos CR (eds) Psychiatry: a world perspective, vol 3. Excerpta Medica, AmsterdamGoogle Scholar
  22. Dahl SG, Hjorth M, Hough E (1981) Chlorpromazine, metrotrimeprazine, and metabolites. Structural changes accompanying the loss of neuroleptic potency by ring sulfoxidation. Mol Pharmacol 21: 409–414Google Scholar
  23. Dahl SG, Hals PA, Johnsen H, Morel E, Lloyd KG (1982) Possible role of hydroxymetabolites in the action of neuroleptics. In: Gram LF, Usdin E, Dahl SG Krag-Sørensen P, Sjoqvist F, Morselli PL (eds) Clinical pharmacology in psychiatry. Macmillan, London, pp 136–149Google Scholar
  24. Dahl-Puustinen ML, Perry TL, Dumont E, von Bahr C, Nordin C, Bertilsson L (1989) Stereoselective disposition of racemin E-10-hydroxynortriptyline in human beings. Chn Pharmacol Ther 45: 650–656CrossRefGoogle Scholar
  25. Della Corte L, Broadhurst AD, Sgaragli GP, Filippini S, Heeley AF, Faravelli C, Pazzagli A (1979) Clinical response and tricyclic plasma levels during treatment with clomipramine. Br J Psychiatry 134: 390–400PubMedCrossRefGoogle Scholar
  26. Faravelli C, Ballerini A, Ambonetti A, Broadhurst AD, Das M (1984) Plasma levels and clinical response during treatment with clomipramine. J Affect Dis 6: 95–107PubMedCrossRefGoogle Scholar
  27. Froemming JS, Francis Lam YW, Jann MW, Davis CM (1989) Pharmacokinetics of haloperidol. Clin Pharmacokinet 17: 396–423PubMedCrossRefGoogle Scholar
  28. Garver DL (1989) Neuroleptic drug levels and antipsychotic effects: a difficult correlation; potential advantage of free (or derivative) versus total plasma levels. J Clin Psychopharmacol 9: 277–281PubMedCrossRefGoogle Scholar
  29. Gex-Fabry M, Balant-Gorgia A, Balant LP, Garrone G (1990) Clomipramine metabolism: model-based analysis of variability factors from drug monitoring data. Clin Pharmacokinet 19: 241–255PubMedCrossRefGoogle Scholar
  30. Guthrie S, Lane EA, Linnoila M (1987) Monitoring of plasma drug concentrations in clinical psychopharmacology. In: Mellzer HY (ed) Psychopharmacology: the third generation of progress. Raven, New York, pp 1323–1338Google Scholar
  31. Jones RB, Luscombe DK (1976) Plasma levels of clomipramine and its N-desmethyl metabolite following oral administration of clomipramine in man. Br J Pharmacol 57: 430 PPubMedGoogle Scholar
  32. Jørgensen A (1986) Metabolism and pharmacokinetics of antipsychotic drugs. Prog Drug Metab 9: 111–174Google Scholar
  33. Ko GN, Korpi ER, Kirch DG (1989) Haloperidol and reduced haloperidol concentrations in plasma and red blood cells from chronic schizophrenic patients. J Clin Psychopharmacol 9: 186–190PubMedCrossRefGoogle Scholar
  34. Lin KM, Finder E (1983) Neuroleptic dosage for Asians. Am J Psychiatry 140: 490–491PubMedGoogle Scholar
  35. Linnoila M, Insel T, Kilts C, Potter WZ, Murphy DL (1982) Plasma steady-state concentrations of hydroxylated metabolites of clomipramine. Clin Pharmacol Ther 32: 208–211PubMedCrossRefGoogle Scholar
  36. Loennechen T, Andersen A, Hals PA, Dahl SG (1990) High-performance liquid chromatographic determination of levomepromazine (metrotrimeprazine) and its mains metabolites in serum and urine. Ther Drug Monit 12: 574–581PubMedCrossRefGoogle Scholar
  37. Lovdahl MJ, Perry PJ, Miller DD (1991) The assay of clozapine and N- Desmethylclozapine in human plasma by high-performance liquid chromatography. Ther Drug Monit 13: 69–72PubMedCrossRefGoogle Scholar
  38. Mackay AVP, Heeley AF, Baker J (1974) The relationship of plasma chlorpromazine to its 7-hydroxy and sulphoxide metabolites in a large population of chronic schizophrenics. Br J Clin Pharmacol 1: 425–430Google Scholar
  39. Marder SR, Van Putten T, Aravagiri M (1989a) Plasma level monitoring for maintenance neuroleptic therapy. In: Dahl SG, Gram LF (eds) Clinical pharmacology in psychiatry. Springer, Berlin Heidelberg New York, pp 269–279 (Psychopharmacology series 7 )Google Scholar
  40. Marder SR, Hubbard JW, Van Putten T, Midha KK (1989b) Pharmacokinetics of long-acting injectable neuroleptic drugs: Clinical implications. Psychopharmacology (Berl) 98: 433–439CrossRefGoogle Scholar
  41. Mårtensson E, Nyberg G (1989) Active metabolites of neuroleptics in plasma and CSF: Implications for therapeutic drug monitoring. In: Dahl SG, Gram LF (eds) Clinical pharmacology in psychiatry. Springer Berlin Heidelberg New York, pp 257–262 (Psychopharmacology series 7)Google Scholar
  42. 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: 189–193PubMedCrossRefGoogle Scholar
  43. Midha KK, Hubbard JW, Cooper JK, Gurnsey T, Hawes EM, McKay G, Chakraborty BS, Yeung PKF (1987a) Therapeutic monitoring of chlorpromazine IV: comparison of a new high-performance liquid chromatographic method with radioimmunoassays for parent drug and some of its major metabolites. Ther Drug Monit 9: 358–365PubMedCrossRefGoogle Scholar
  44. Midha KK, Hubbard JW, Marder SR, Hawes EM, Van Putten T, McKay G, May PRA (1987b) The sulfoxidation of fluphenazine in schizophrenic patients maintained on fluphenazine decanoate. Psychopharmacology (Berl) 93: 369–373CrossRefGoogle Scholar
  45. Midha KK, Cooper JK, Hawes EM, Hubbard JW, Korchinski ED, McKay G (1988) An ultrasensitive method for measurement of haloperidol and reduced haloperidol in plasma by high-performance liquid chromatography with coulometric detection. Ther Drug Monit 10: 177–183PubMedCrossRefGoogle Scholar
  46. Midha KK, Chakraborty BS, Ganes DA, Hawes EM, Hubbard JW, Keegan DL, Korchinski ED, McKay G (1989) Intersubject variation in the pharmacokinetics of haloperidol and reduced haloperidol. J Clin Psychopharmacol 9: 98–104PubMedCrossRefGoogle Scholar
  47. Montgomery SA, McAuley R, Montgomery DB, Braithwaite RA, Dawling S (1979) Dosage adjustment from simple nortriptyline spot level predictor tests in depressed patients. Clin Pharmacokinet 4: 129–136PubMedCrossRefGoogle Scholar
  48. Montgomery SA, McAuley R, Montgomery DB, Dawling S, Braithwaite RA (1980) Plasma concentration of clomipramine and desmethylclomipramine and clinical response in depressed patients. Postgrad Med J 56 Suppl 1: 130–133Google Scholar
  49. Montgomery SA, Baldwin D, Shah A, Fineberg N, Montgomery D (1990) Plasma-level response with fluoxetine and zimelidine. Clin Neuropharmacol 13 Suppl 1: S71–S75Google Scholar
  50. Moyes ICA, Ray RL, Moyes RB (1980) Plasma levels and clinical improvement: a comparative study of clomipramine and amitriptyline in depression. Postgrad Med J 56 Suppl 1: 127–129Google Scholar
  51. Nelson JC, Jatlow PI (1987) Nonlinear desipramine kinetics: prevalence and importance. Clin Pharmacol Ther 6: 666–670CrossRefGoogle Scholar
  52. Nelson JC, Bock JL, Jatlow PI (1983) Clinical implications of 2-hydroxydesipramine plasma concentrations. Clin Pharmacol Ther 33: 183–189PubMedCrossRefGoogle Scholar
  53. Nelson JC, Jatlow PI, Mazure C (1987) Rapid desipramine dose adjustment using 24-hour levels. Clin Psychopharmacol 7: 72–77Google Scholar
  54. Nelson JC, Mazure C, Jatlow PI (1988a) Antidepressant activity of 2-hydroxydesipramine. Clin Pharmacol Ther 44: 283–288PubMedCrossRefGoogle Scholar
  55. Nelson JC, Atillasoy E, Mazure C, Jatlow PI (1988b) Hydroxydesipramine in the elderly. J Clin Psychopharmacol 8: 428–433PubMedCrossRefGoogle Scholar
  56. Nelson JC, Mazure C, Jatlow PI (1989) Clinical implications of the pharmacokinetics of tricyclic antidepressants. In: Dahl SG, Gram LF (eds) Clinical pharmacology in psychiatry. Springer, Berlin Heidelberg New York, pp 219–227 (Psychopharmacology series 7 )Google Scholar
  57. Nordin C, Bertilsson L, Siwers B (1987) Clinical and biochemical effects during treatment of depression with nortriptyline: the role of 10-hydroxynortriptyline. Clin Pharmacol Ther 42: 10–19PubMedCrossRefGoogle Scholar
  58. Pollock BG, Perel JM (1989) Hydroxy metabolites of tricyclic antidepressants: evaluation of relative cardiotoxicity. In: Dahl SG, Gram LF (eds) Clinical pharmacology in psychiatry. Springer, Berlin Heidelberg New York, pp 232–236 (Psychopharmacology series 7 )Google Scholar
  59. Potkin DG, Shen YC, Pardes H, Phelps BH, Zhou DF, Shu L, Korpi ER, Wyatt RJ (1984) Haloperidol concentration elevated in Chinese patients. Psychiatry Res 12: 167–172PubMedCrossRefGoogle Scholar
  60. Potter WZ (1981) Active metabolites of tricyclic antidepressants. In: Usdin E, Dahl SG, Gram LF, Lingjaerde O (eds) Clinical pharmacology in psychiatry. Macmillan, London, pp 139–153Google Scholar
  61. Potter WZ, Calil HM, Sutfin TA, Zavadil AP, Jusko WJ, Rapoport J, Goodwin FK (1982) Active metabolites of imipramine and desipramine. Clin Pharmacol Ther 31: 393–401PubMedCrossRefGoogle Scholar
  62. Reisby N, Gram LF, Bech P, Sihm F, Krautwald O, Elley J, Christiansen J (1979) Clomipramine: plasma levels and clinical effects. Commun Psychopharmacol 3: 341–351PubMedGoogle Scholar
  63. Rigal JG, Albin HC, Duchier AR, D’Aulnay JM, Fenelon JH, Vincon GA, Demotes-Mainard FM (1987) Imipramine blood levels and clinical outcome. J Clin Psychopharmacol 7: 222–229PubMedCrossRefGoogle Scholar
  64. Schneider LS, Cooper TB, Severson JA, Zemplenyi T, Sloane RB (1988) Electrocardiographic changes with nortriptyline and 10-hydroxynortriptyline in elderly depressed outpatients. J Clin Psychopharmacol 8: 402–408PubMedCrossRefGoogle Scholar
  65. Schneider LS, Cooper TB, Suckow RF, Lyness SA, Haugen C, Palmer R, Sloane RB (1990) Relationship of hydroxy nortriptyline to nortriptyline concentration and creatinine clearance in depressed elderly outpatients. J Clin Psychopharmacol 10: 333–337PubMedCrossRefGoogle Scholar
  66. Shostak M, Perel JM, Stiller RL, Wyman W, Curran S (1987) Plasma haloperidol and clinical response. A role for reduced haloperidol in antipsychotic activity? J Clin Psychopharmacol 7: 394–400PubMedCrossRefGoogle Scholar
  67. Sindrup SH, Brøsen K, Gram LF (1990) Nonlinear kinetics of imipramine in low and medium plasma level ranges. Ther Drug Monit 12: 445–449PubMedCrossRefGoogle Scholar
  68. Slattery JT, Gibaldi M, Koup JR (1980) Prediction of maintenance dose required to attain a desired drug concentration at steady-state from a single determination of concentration after an initial dose. Clin Pharmacokinet 5: 377–385PubMedCrossRefGoogle Scholar
  69. Someya T, Takahashi S, Shibasaki M, Inaba T, Cheung SW, Tang SW (1990) Reduced haloperidol/haloperidol ratios in plasma: polymorphism in Japanese psychiatric patients. Psychiatry Res 31: 111–120PubMedCrossRefGoogle Scholar
  70. Stern SL, Ribner HS, Cooper TB, Nelson LD, Johnson MH, Suckow RF (1991) 2-Hydroxydesipramine and desipramine plasma levels and electrocardiographic effects in depressed younger adults. J Clin Psychopharmacol 11:93–98PubMedCrossRefGoogle Scholar
  71. Sutfin TA, Perini GI, Molnar G, Jusko WJ (1988) Multiple-dose pharmacokinetics of imipramine and its major active and conjugated metabolites in depressed patients. J Clin Psychopharmacol 8: 48–53PubMedCrossRefGoogle Scholar
  72. 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: 15–20PubMedCrossRefGoogle Scholar
  73. Vandel S, Bertschy G, Vandel B, Allers G, Volmat R (1989) Amitriptyline: linear or nonlinear kinetics in every day practice? Eur J Pharmacol 37: 595–598Google Scholar
  74. Vandel S, Bertschy G, Allers G, Volmat R (1990) Nonlinear Kinetics of nortriptyline in every day practice. Eur J Clin Pharmacol 39: 97–98PubMedCrossRefGoogle Scholar
  75. Von Bahr C, Movin G, Nordin C, Lidén A, Hammarlund-Udenaes M, Hedberg A, Ring H, Sjöqvist F (1991) Plasma levels of thioridazine and metabolites are influenced by the debrisoquin hydroxylation phenotype. Clin Pharmacol Ther 49: 234–240CrossRefGoogle Scholar
  76. Wode-Helgodt B, Alfredsson G (1981) Concentrations of chlorpromazine and two of its active metabolites in plasma and cerebrospinal fluid of psychotic patients treated with fixed drug doses. Psychopharmacology (Berl) 73: 55–62CrossRefGoogle Scholar
  77. Young RC, Dhar AK, Kutt H, Alexopoulos GS (1988) Isomers of 10-hydroxynortriptyline in geriatric depression. Ther Drug Monit 10: 164–167PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • A. E. Balant-Gorgia
    • 1
  • L. P. Balant
    • 2
  1. 1.Therapeutic Drug Monitoring UnitInstitutions Universitaires de PsychiatrieChêne-BourgSwitzerland
  2. 2.Clinical Research UnitInstitutions Universitaires de PsychiatrieGenevaSwitzerland

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