Advertisement

CNS Drugs

, Volume 5, Issue 3, pp 200–223 | Cite as

Polymorphic Drug Oxidation

Relevance to the Treatment of Psychiatric Disorders
  • Leif Bertilsson
  • Marja-Liisa Dahl
Review Articles Clinical Concepts

Summary

Plasma drug concentrations and response to drugs vary considerably between patients during treatment with psychotropic drugs. Many antidepressant and antipsychotic drugs are metabolised by the polymorphic debrisoquine/sparteine hydroxylase, i.e. cytochrome P450 (CYP) 2D6, which is absent in 7% of Caucasians [these individuals are termed ‘poor metabolisers’ (PM)]. Such PM might develop adverse drug reactions while receiving usual dosages of drugs due to high plasma drug concentrations. In contrast, ultrarapid metabolisers with multiple CYP2D6 genes might require high doses of such drugs for optimal therapy.

The mean CYP2D6 activity is lower in Oriental than in Caucasian populations, because of a frequent mutation in exon 1 of CYP2D6, causing decreased enzyme activity. This may partly explain the use of lower doses of antidepressants and antipsychotics in Oriental than in Caucasian individuals. In contrast to other antipsychotics, clozapine is not metabolised by CYP2D6 to a major extent, but by CYP1A2. This latter isozyme is induced by tobacco smoking.

The hydroxylation of S-mephenytoin is catalysed by the polymorphic CYP2C19 isozyme. About 3% of Caucasians, but as many as 12 to 20% of Oriental persons, are PM of S-mephenytoin and of omeprazole, another CYP2C19 substrate. Among psychotropic drugs, tertiary amine antidepressants (amitrip-tyline, citalopram, clomipramine and imipramine) are N-demethylated by CYP2C19. Both diazepam and its demethyl metabolite are partly metabolised by this polymorphic enzyme. The high incidence of PM (and of heterozygous extensive metabolisers) of S-mephenytoin in Asia might be the reason for the reported higher sensitivity of Orientals to diazepam compared with Caucasians.

Various probe drugs may be used for phenotyping of CYP2D6 (debrisoquine, dextromethorphan and sparteine) and CYP2C19 (mephenytoin and omeprazole). Allele-specific polymerase chain reaction (PCR)-based methods are now available for genotyping using leucocyte DNA. A major advantage of genotyping over phenotyping is that the former may be performed using blood samples from patients irrespective of treatment with psychotropic drugs.

Keywords

Haloperidol Clozapine Fluvoxamine Desipramine Nortriptyline 
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. 1.
    Hammer W, Sjöqvist F. Plasma levels of monomethylated tricyclic antidepressants during treatment with imipramine-like compounds. Life Sci 1967; 6: 1895–903PubMedGoogle Scholar
  2. 2.
    Dahl SG. Plasma level monitoring of antipsychotic drugs. Clin Pharmacokinet 1986; 11: 36–61PubMedGoogle Scholar
  3. 3.
    Kalow W, editor. Pharmacogenetics of drug metabolism. New York: Pergamon Press, Inc., 1992Google Scholar
  4. 4.
    Gonzalez FJ. Human cytochromes P450: problems and prospects. Trends Pharmacol Sci 1992; 13: 346–52PubMedGoogle Scholar
  5. 5.
    Mahgoub A, Idle JR, Dring DG, et al. Polymorphic hydroxylation of debrisoquine in man. Lancet 1977; 2: 584–6PubMedGoogle Scholar
  6. 6.
    Tucker GT, Silas JH, Iyun AO, et al. Polymorphic hydroxy lation of debrisoquine in man [letter]. Lancet 1977; 2: 718PubMedGoogle Scholar
  7. 7.
    Eichelbaum M, Spannbrucker N, Steinke B, et al. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol 1979; 16: 183–7PubMedGoogle Scholar
  8. 8.
    Eichelbaum M, Bertilsson L, Säwe J, et al. Polymorphic oxidation of sparteine and debrisoquine: related pharmacogenetic entities. Clin Pharmacol Ther 1982; 31: 184–6PubMedGoogle Scholar
  9. 9.
    Wilkinson GR, Guengerich FP, Branch RA. Genetic polymorphism of S-mephenytoin hydroxylation. In: Kalow W, editor. Pharmacogenetics of drug metabolism. New York: Pergamon Press, 1992: 657–85Google Scholar
  10. 10.
    Wrighton SA, Stevens JC, Becker GW, et al. Isolation and characterization of human liver cytochrome P4502C19: correlation between 2C19 and S-mephenytoin 4′-hydroxylation. Arch Biochem Biophys 1993; 306: 240–5PubMedGoogle Scholar
  11. 11.
    Goldstein JA, Faletto MB, Romkes-Sparks M, et al. Evidence that CYP2C19 is the major (S)-mephenytoin 4′-hydroxylase in humans. Biochemistry 1994; 33: 1743–52PubMedGoogle Scholar
  12. 12.
    Evans DA, Mahgoub A, Sloan TP, et al. A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population. J Med Genet 1980; 17: 102–5PubMedGoogle Scholar
  13. 13.
    Alván G, Bechtel P, Iselius L, et al. Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol 1990; 39: 533–7PubMedGoogle Scholar
  14. 14.
    Bertilsson L, Lou YQ, Du YL, et al. Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquine and S-mephenytoin. Clin Pharmacol Ther 1992; 51: 388–97PubMedGoogle Scholar
  15. 15.
    Masimirembwa CM. Pharmacogenetics of drug metabolising enzymes in a black African population [thesis]. Stockholm: Karolinska Institute, 1995Google Scholar
  16. 16.
    Masimirembwa C, Bertilsson L, Johansson I, et al. Phenotyping and genotyping of S-mephenytoin hydroxylase (cytochrome P450 2C19) in a Shona population of Zimbabwe. Clin Pharmacol Ther 1995; 37: 656–61Google Scholar
  17. 17.
    Gonzalez FJ, Matsunaga T, Nagata K, et al. Debrisoquine 4-hydroxylase: characterization of a new P450 gene family, regulation, chromosomal mapping and molecular analysis of the DA rat polymorphism. DNA 1987; 6: 149–61PubMedGoogle Scholar
  18. 18.
    Zanger UM, Vilbois F, Hardwick JP, et al. Absence of hepatic cytochrome P450bufI causes genetically deficient debrisoquine oxidation in man. Biochemistry 1988; 27: 5447–54PubMedGoogle Scholar
  19. 19.
    Kagimoto M, Heim M, Kagimoto K, et al. Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolisers of debrisoquine. J Biol Chem 1990; 265: 17209–14PubMedGoogle Scholar
  20. 20.
    Heim M, Meyer UA. Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification. Lancet 1990; 336: 529–32PubMedGoogle Scholar
  21. 21.
    Gough AC, Miles JS, Spurr NK, et al. Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature 1990; 347: 773–6PubMedGoogle Scholar
  22. 22.
    Gaedigk A, Blum M, Gaedigk R, et al. Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism. Am J Hum Genet 1991; 48: 943–50PubMedGoogle Scholar
  23. 23.
    Broly F, Gaedigk A, Heim M, et al. Debrisoquine/sparteine hydroxylation genotype and phenotype: analysis of common mutations and alleles of CYP2D6 in a European population. DNA Cell Biol 1991; 10: 545–58PubMedGoogle Scholar
  24. 24.
    Dahl M-L, Johansson I, Porsmyr Palmertz M, et al. Analysis of the CYP2D6 gene in relation to debrisoquin and desipramine hydroxylation in a Swedish population. Clin Pharmacol Ther 1992; 51: 12–7PubMedGoogle Scholar
  25. 25.
    Johansson I, Oscarsson M, Yue QY, et al. Genetic analysis of the Chinese CYP2D6 locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 1994; 46: 452–9PubMedGoogle Scholar
  26. 26.
    Masimirembwa CM, Johansson I, Hasler JA, et al. Genetic polymorphism of cytochrome P450 2D6 in Zimbabwean population. Pharmacogenetics 1993; 3: 275–80PubMedGoogle Scholar
  27. 27.
    Evans WE, Relling MV, Rahman A, et al. Genetic basis for a lower prevalence of deficient CYP2D6 oxidative drug metabolism phenotypes in black Americans. J Clin Invest 1993; 91: 2150–4PubMedGoogle Scholar
  28. 28.
    Johansson I, Lundqvist E, Bertilsson L, et al. Inherited amplification of an active gene in the cytochrome P450 CYP2D-locus as a cause of ultrarapid metabolism of debrisoquine. Proc Natl Acad Sci USA 1993; 90: 11825–9PubMedGoogle Scholar
  29. 29.
    Bertilsson L, Dahl M-L, Ingelman-Sundberg M, et al. Interindividual and interethnic differences in polymorphic drug oxidation: implication for drug therapy with focus on psychoactive drugs. In: Pacifici GM, Fracchia GN, editors. Advances in drug metabolism in man. Brussels: European Commission, 1995: 85–136Google Scholar
  30. 30.
    Tyndale R, Aoyama T, Broly F, et al. Identification of a new variant CYP2D6 allele lacking the codon encoding Lys-281: possible association with the poor metabolizer phenotype. Pharmacogenetics 1991; 1: 26–32PubMedGoogle Scholar
  31. 31.
    Broly F, Meyer UA. Debrisoquine oxidation polymorphism: phenotypic consequences of a 3-base-pair deletion in exon 5 of the CYP2D6 gene. Pharmacogenetics 1993; 3: 123–30PubMedGoogle Scholar
  32. 32.
    Bertilsson L, Dahl M-L, Sjöqvist F, et al. Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine [letter]. Lancet 1993; 341: 63PubMedGoogle Scholar
  33. 33.
    Dahl M-L, Johansson I, Bertilsson L, et al. Ultrarapid hydroxylation of debrisoquine in a Swedish population. Analysis of the molecular genetic basis. J Pharmacol Exp Ther 1995; 274: 516–20PubMedGoogle Scholar
  34. 34.
    Nakamura K, Goto F, Ray WA, et al. Interethnic differences in genetic polymorphism of debrisoquine and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther 1985; 38: 402–8PubMedGoogle Scholar
  35. 35.
    Sohn D-R, Shin S-G, Park C-W, et al. Metoprolol oxidation polymorphism in a Korean population: comparison with native Japanese and Chinese populations. Br J Clin Pharmacol 1991; 32: 504–7PubMedGoogle Scholar
  36. 36.
    Johansson I, Yue QY, Dahl M-L, et al. Genetic analysis of the interethnic difference between Chinese and Caucasians in the polymorphic metabolism of debrisoquine and codeine. Eur J Clin Pharmacol 1991; 40: 553–6PubMedGoogle Scholar
  37. 37.
    Yokota H, Tamura S, Furuya H, et al. Evidence for a new variant CYP2D6 allele CYP2D6J in a Japanese population associated with lower in vivo rates of sparteine metabolism. Pharmacogenetics 1993; 3: 256–63PubMedGoogle Scholar
  38. 38.
    Dahl M-L, Yue Q-Y, Roh H-K, et al. Genetic analysis of the CYP2D locus in relation to debrisoquine hydroxylation capacity in Korean, Japanese and Chinese subjects. Pharmacogenetics 1995; 5: 159–64PubMedGoogle Scholar
  39. 39.
    Kalow W. Interethnic variation of drug metabolism. Trends Pharmacol Sci 1991; 12: 102–7PubMedGoogle Scholar
  40. 40.
    de Morais SMF, Wilkinson GR, Blaisdell J, et al. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 1994; 269: 15419–22PubMedGoogle Scholar
  41. 41.
    Nei M, Saitou N. Genetic relationship of human populations and ethnic differences in reactions to drugs and food. In: Kalow W, Goedde HW, Agarwal DP, editors. Ethnic differences in reactions to drugs and xenobiotics. New York: Alan R Liss, 1986: 21–37Google Scholar
  42. 42.
    de Morais SMF, Wilkinson GR, Blaisdell J, et al. Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol 1994; 46: 594–8PubMedGoogle Scholar
  43. 43.
    Chang M, Dahl M-L, Tybring G, et al. Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians. Comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype. Pharmacogenetics 1995; 5: 358–63PubMedGoogle Scholar
  44. 44.
    Wedlund PJ, Aslanian WS, McAllister CB, et al. Mephenytoin hydroxylation deficiency in Caucasians: frequency of a new oxidative drug metabolism polymorphism. Clin Pharmacol Ther 1984; 36: 773–80PubMedGoogle Scholar
  45. 45.
    Sanz EJ, Villen T, Alm C, et al. S-mephenytoin hydroxylation phenotype in a Swedish population determined after co-administration with debrisoquin. Clin Pharmacol Ther 1989; 45: 495–9PubMedGoogle Scholar
  46. 46.
    Jurima M, Inaba T, Kadar D, et al. Genetic polymorphism of mephenytoin p(4′)-hydroxylation: difference between Orientals and Caucasians. Br J Clin Pharmacol 1985; 19: 483–7PubMedGoogle Scholar
  47. 47.
    Horai Y, Nakano M, Ishizaki T, et al. Metoprolol and mephenytoin oxidation polymorphisms in Far Eastern Oriental subjects: Japanese versus mainland Chinese. Clin Pharmacol Ther 1989; 46: 198–207PubMedGoogle Scholar
  48. 48.
    Sohn DR, Kusaka M, Ishizaki T, et al. Incidence of S-mephenytoin hydroxylation deficiency in a Korean population and the interphenotypic differences in diazepam pharmacokinetics. Clin Pharmacol Ther 1992; 52: 160–9PubMedGoogle Scholar
  49. 49.
    Skjelbo E, Brøsen K, Hallas J, et al. The mephenytoin oxidation polymorphism is partially responsible for the N-demethylation of imipramine. Clin Pharmacol Ther 1991; 49: 18–23PubMedGoogle Scholar
  50. 50.
    Ward SA, Helsby NA, Skjelbo E, et al. The activation of the biguanide antimalarial proguanil co-segregates with the mephenytoin oxidation polymorphism — a panel study. Br J Clin Pharmacol 1991; 31: 689–92PubMedGoogle Scholar
  51. 51.
    Rudorfer MV, Potter WZ. Pharmacokinetics of antidepressants. In: Meltzer HY, editor. Psychopharmacology: the third generation of progress. New York: Raven Press, 1987: 1353–63Google Scholar
  52. 52.
    Nordin C, Bertilsson L. Active hydroxymetabolites of antidepressants: emphasis on E-10-hydroxy-nortriptyline. Clin Pharmacokinet 1995; 28: 26–40PubMedGoogle Scholar
  53. 53.
    Alexanderson B, Evans DAP, Sjöqvist F. Steady-state plasma levels of nortriptyline in twins: influence of genetic factors and drug therapy. BMJ 1969; 2: 764–8Google Scholar
  54. 54.
    Åsberg M, Evans DAP, Sjöqvist F. Genetic control of nortriptyline kinetics in man: a study of relatives of propositi with high plasma concentrations. J Med Genet 1971; 8: 129–35PubMedGoogle Scholar
  55. 55.
    Hammer W, Mårtens S, Sjöqvist F. Comparative studies of the metabolism of desmethylimipramine, nortriptyline and ox-phenylbutazone in man. Clin Pharmacol Ther 1969; 10: 44–6PubMedGoogle Scholar
  56. 56.
    Alexanderson B. Pharmacokinetics of desmethylimipramine and nortriptyline in man after single and oral doses — a crossover study. Eur J Clin Pharmacol 1972; 5: 7–10Google Scholar
  57. 57.
    Mellström B, Bertilsson L, Träskman L, et al. Intraindividual similarity in the metabolism of amitriptyline and chlorimipramine in depressed patients. Pharmacology 1979; 19: 282–7PubMedGoogle Scholar
  58. 58.
    Alexanderson B, Borgå O. Urinary excretion of nortriptyline and five of its metabolites in man after single and multiple oral doses. Eur J Clin Pharmacol 1973; 5: 174–80Google Scholar
  59. 59.
    Bertilsson L, Alexanderson B. Stereospecific hydroxylation of nortriptyline in man in relation to interindividual differences in its steady-state plasma level. Eur J Clin Pharmacol 1972; 4: 201–5Google Scholar
  60. 60.
    Bertilsson L, Eichelbaum M, Mellström B, et al. Nortriptyline and antipyrine clearance in relation to debrisoquine hydroxylation in man. Life Sci 1980; 27: 1673–7PubMedGoogle Scholar
  61. 61.
    Mellström B, Bertilsson L, Säwe J, et al. E- and Z-10-hydroxylation of nortriptyline: relationship to polymorphic debrisoquine hydroxylation. Clin Pharmacol Ther 1981; 30: 189–93PubMedGoogle Scholar
  62. 62.
    Mellström B, Bertilsson L, Birgersson C, et al. E- and Z-10-hydroxylation of nortriptyline by human liver microsomes — methods and characterization. Drug Metab Disp 1983; 11: 115–9Google Scholar
  63. 63.
    Nordin C, Siwers B, Benitez J, et al. Plasma concentrations of nortriptyline and its 10-hydroxy metabolite in depressed patients — relationship to the debrisoquine metabolic ratio. Br J Clin Pharmacol 1985; 19: 832–5PubMedGoogle Scholar
  64. 64.
    Gram LF, Brøsen K, Kragh-Sørensen P, et al. 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 1989; 11: 508–14PubMedGoogle Scholar
  65. 65.
    Nordin C, Bertilsson L, Siwers B. Clinical and biochemical effects during treatment of depression with nortriptyline: the role of 10-hydroxy-nortriptyline. Clin Pharmacol Ther 1987; 42: 10–9PubMedGoogle Scholar
  66. 66.
    Potter WZ, Bertilsson L, Sjöqvist F. Clinical pharmacokinetics of psychotropic drugs — fundamental and practical aspects. In: van Praag HM, Lader MH, Rafaelson OJ, et al., editors. Handbook of biological psychiatry: part VI. New York: Marcel Dekker lnc., 1981: 71–134Google Scholar
  67. 67.
    Bertilsson L, Åberg-Wistedt A. The debrisoquine hydroxylation test predicts steady-state plasma levels of desipramine. Br J Clin Pharmacol 1983; 15: 388–90PubMedGoogle Scholar
  68. 68.
    Spina E, Birgersson C, von Bahr C, et al. Phenotypic consistency in hydroxylation of desmethylimipramine and debrisoquine in healthy subjects and in human liver microxomes. Clin Pharmacol Ther 1984; 36: 677–82PubMedGoogle Scholar
  69. 69.
    Spina E, Steiner E, Ericsson O, et al. Hydroxylation of desmethylimipramine: dependence on the debrisoquin hydroxylation phenotype. Clin Pharmacol Ther 1987; 41: 314–9PubMedGoogle Scholar
  70. 70.
    Dahl M-L, Iselius L, Alm C, et al. Polymorphic 2-hydroxylation of desipramine: a population and family study. Eur J Clin Pharmacol 1993; 44: 445–50PubMedGoogle Scholar
  71. 71.
    Balant-Gorgia AE, Schultz P, Dayer P, et al. Role of oxidation polymorphism on blood and urine concentrations of amitriptyline and its metabolites in man. Arch Psychiatr Nervenkr 1982; 232: 215–22PubMedGoogle Scholar
  72. 72.
    Balant-Gorgia AE, Balant LP, Genet Ch, et al. Importance of oxidative polymorphism and levomepromazine treatment on the steady-state blood concentrations of clomipramine and its major metabolites. Eur J Clin Pharmacol 1986; 31: 449–55PubMedGoogle Scholar
  73. 73.
    Mellström B, Bertilsson L, Lou Y-C, et al. Amitriptyline metabolism: relationship to polymorphic debrisoquine hydroxylation. Clin Pharmacol Ther 1983; 34: 516–20PubMedGoogle Scholar
  74. 74.
    Mellström B, Säwe J, Bertilsson L, et al. Amitriptyline metabolism: association with debrisoquin hydroxylation in non-smokers. Clin Pharmacol Ther 1986; 39: 369–71PubMedGoogle Scholar
  75. 75.
    Coutts RT, Su P, Baker GB. Involvement of CYP2D6, CYP3A4, and other cytochrome P-450 isozymes in N-dealkylation reactions. J Pharmacol Toxicol Methods 1994; 31: 177–86PubMedGoogle Scholar
  76. 76.
    Dahl M-L, Tybring G, Elwin C-E, et al. Stereoselective disposition of mianserin is related to debrisoquine hydroxylation polymorphism. Clin Pharmacol Ther 1994; 56: 176–83PubMedGoogle Scholar
  77. 77.
    Firkusny L, Gleiter H. Maprotiline metabolism appears to cosegregate with the genetically-determined CYP2D6 polymorphic hydroxylation of debrisoquine. Br J Clin Pharmacol 1994; 37: 383–8PubMedGoogle Scholar
  78. 78.
    Sindrup SH, Brøsen K, Gram LF, et al. The relationship between paroxetine and the sparteine oxidation polymorphism. Clin Pharmacol Ther 1992; 51: 278–87PubMedGoogle Scholar
  79. 79.
    Sindrup SH, Brøsen K, Hansen MGJ, et al. Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms. Ther Drug Monit 1993; 15: 11–7PubMedGoogle Scholar
  80. 80.
    Brøsen K. The pharmacogenetics of the selective serotonin reuptake inhibitors. Clin Invest 1993; 71: 1002–9Google Scholar
  81. 81.
    Gram LF, Guentert TW, Grange S, et al. Moclobemide, a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6 and CYP1A2: a panel study. Clin Pharmacol Ther 1995; 57: 670–7PubMedGoogle Scholar
  82. 82.
    Sellers EM, Ball SE, Cheung SW, et al. Inhibition by venlafaxine (VF) and other 5HT uptake inhibitors of the polymorphic enzyme CYP2D6 [abstract]. 22nd Annual Meeting of the American College of Neuropsychopharmacology; 1993 Dec 13–17; Honolulu, 163Google Scholar
  83. 83.
    Gram LF. Plasma level monitoring of tricyclic antidepressant therapy. Clin Pharmacokinet 1977; 2: 237–51PubMedGoogle Scholar
  84. 84.
    Preskorn SH, Dorey RC, Jerkovich GS. Therapeutic drug monitoring of tricyclic antidepressants. Clin Chem 1988; 34: 822–8PubMedGoogle Scholar
  85. 85.
    Åsberg M, Cronholm B, Sjöqvist F, et al. Relationship between plasma level and therapeutic effect of nortriptyline. BMJ 1971; 3: 331–4PubMedGoogle Scholar
  86. 86.
    Bertilsson L, Mellström B, Sjöqvist F, et al. Slow hydroxylation of nortriptyline and concomitant poor debrisoquine hydroxylation: clinical implication. Lancet 1981; 1: 560–1PubMedGoogle Scholar
  87. 87.
    Sjöqvist F, Bertilsson L. Clinical pharmacology of antidepressant drugs: pharmacogenetics. In: Usdin E, Åsberg M, Bertilsson L, et al., editors. Frontiers in biochemical and pharmacological research in depression. New York: Raven Press, 1984: 359–72Google Scholar
  88. 88.
    Sjöqvist F, Bertilsson L. Slow hydroxylation of tricyclic antidepressants — relationship to polymorphic drug oxidation. In: Kalow W, Goedde HW, Agarwal DP, editors. Ethnic differences in reactions to drugs and xenobiotics. New York: Alan R Liss Inc., 1986: 169–88Google Scholar
  89. 89.
    Balant-Gorgia AE, Balant LP, Garrone G. High blood concentrations of imipramine or clomipramine and therapeutic failure: a case report study using drug monitoring data. Ther Drug Monit 1989; 11: 415–20PubMedGoogle Scholar
  90. 90.
    Brøsen K, Klysner R, Gram LF, et al. Steady-state levels of imipramine and its metabolites in relation to the sparteine/debrisoquine polymorphism. Eur J Clin Pharmacol 1986; 30: 679–84PubMedGoogle Scholar
  91. 91.
    Bertilsson L, Åberg-Wistedt A, Gustafsson LL, et al. Extremely rapid hydroxylation of debrisoquine: a case report with implication for treatment with nortriptyline and other tricyclic antidepressants. Ther Drug Monit 1985; 7: 478–80PubMedGoogle Scholar
  92. 92.
    Rudorfer MV, Lane EA, Chang WH, et al. Desipramine pharmacokinetics in Chinese and Caucasian volunteers. Br J Clin Pharmacol 1984; 17: 433–40PubMedGoogle Scholar
  93. 93.
    Chan K, Chiun H, Lee S, et al. Estimating plasma concentrations of desipramine in Chinese depressed patients using the repeated one-point method. Br J Clin Pharmacol 1988; 26; 638–9PGoogle Scholar
  94. 94.
    Lin KM, Poland RE, Smith MW, et al. Pharmacokinetic and other related factors affecting psychotropic responses in Asians. Psychopharmacol Bull 1991; 27: 427–39PubMedGoogle Scholar
  95. 95.
    Brøsen K, Gram LF. Clinical significance of the sparteine/debrisoquine oxidation polymorphism. Eur J Clin Pharmacol 1989; 36: 537–47PubMedGoogle Scholar
  96. 96.
    Cooke RG, Warsh JJ, Stancer HC, et al. The nonlinear kinetics of desipramine and 2-hydroxydesipramine in plasma. Clin Pharmacol Ther 1984; 36: 343–9PubMedGoogle Scholar
  97. 97.
    Brøsen K, Gram LF, Klysner R, et al. Steady-state levels of imipramine and its metabolites: significance of dose-dependent kinetics. Eur J Clin Pharmacol 1986; 30: 43–9PubMedGoogle Scholar
  98. 98.
    Sindrup SH, Brøsen K, Gram LF. Nonlinear kinetics of imipramine in low and medium plasma level ranges. Ther Drug Monit 1990; 12: 445–9PubMedGoogle Scholar
  99. 99.
    Brøsen K, Gram LF. First-pass metabolism of imipramine and desipramine: impact of the sparteine oxidation phenotype. Clin Pharmacol Ther 1988; 43: 400–6PubMedGoogle Scholar
  100. 100.
    von Bahr C, Spina E, Birgersson C, et al. Inhibition of desmethylimipramine 2-hydroxylation by drugs in human liver microsomes. Biochem Pharmacol 1985; 34: 2501–5Google Scholar
  101. 101.
    Hirschowitz J, Bennet JA, Zemlan FP, et al. Thioridazine effect on desipramine plasma levels. J Clin Psychopharmacol 1983; 3: 376–9PubMedGoogle Scholar
  102. 102.
    Inaba T, Jurima M, Mahon WA, et al. In vitro inhibition studies of two isozymes of human liver cytochrome P-450. Mephenytoin p-hydroxylase and sparteine monooxygenase. Drug Metab Dispos 1985; 13: 443–8PubMedGoogle Scholar
  103. 103.
    Gram LF, Fredricson-Overø K. Drug interaction: inhibitory effect of neuroleptics on metabolism of tricyclic antidepressants in man. BMJ 1972: 1: 463–5PubMedGoogle Scholar
  104. 104.
    Goff DC, Baldessarini RJ. Drug interactions with antipsychotic agents. J Clin Psychopharmacol 1993; 13: 57–67PubMedGoogle Scholar
  105. 105.
    Jerling M, Bertilsson L, Sjöqvist F. The use of therapeutic drug monitoring data to document kinetic drug interactions: an example with amitriptyline and nortriptyline. Ther Drug Monit 1994; 16: 1–12PubMedGoogle Scholar
  106. 106.
    Crewe HR, Lennard MS, Tucker GT, et al. The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol 1992; 34: 262–5PubMedGoogle Scholar
  107. 107.
    Brpsen K, Skjelbo E, Rasmussen BB, et al. Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol 1993; 45: 1211–4Google Scholar
  108. 108.
    Bertschy G, Vandel S, Vandel R, et al. Fluvoxamine tricyclic antidepressant interaction: an accidental finding. Eur J Clin Pharmacol 1991; 40: 119–20PubMedGoogle Scholar
  109. 109.
    Spina E, Campo GM, Avenso A, et al. Interaction between fluvoxamine and imipramine/desipramine in four patients. Ther Drug Monit 1992; 14: 194–6PubMedGoogle Scholar
  110. 110.
    Spina E, Pollicino AM, Avenso A, et al. Effect of fluvoxamine on the pharmacokinetics of imipramine and desipramine in healthy subjects. Ther Drug Monit 1993; 15: 243–6PubMedGoogle Scholar
  111. 111.
    Baldessarini RJ, Cohen BM, Teicher MH. Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses. Arch Gen Psychiatry 1988; 45: 79–91PubMedGoogle Scholar
  112. 112.
    Dahl ML, Bertilsson L. Genetically variable metabolism of antidepressants and neuroleptic drugs in man. Pharmacogenetics 1993; 3: 61–70PubMedGoogle Scholar
  113. 113.
    Syvälahti EKG, Lindberg R, Kallio J, et al. Inhibitory effects of neuroleptics on debrisoquine oxidation in man. Br J Clin Pharmacol 1986; 22: 89–92PubMedGoogle Scholar
  114. 114.
    Dahl-Puustinen M-L, Lidén A, Alm C, et al. Disposition of perphenazine is related to polymorphic debrisoquin hydroxylation in human beings. Clin Pharmacol Ther 1989; 46: 78–81PubMedGoogle Scholar
  115. 115.
    Dahl M-L, Ekqvist B, Widén J, et al. Disposition of the neuroleptic zuclopenthixol cosegregates with the polymorphic hydroxylation of debrisoquine in humans. Acta Psychiatr Scand 1991; 84: 99–102PubMedGoogle Scholar
  116. 116.
    Froemming JS, Francis Lam YW, Jann MW, et al. Pharmacokinetics of haloperidol. Clin Pharmacokinet 1989; 17: 396–423PubMedGoogle Scholar
  117. 117.
    Chakraborty BS, Hubbard JW, Hawes EM, et al. Interconversion between haloperidol and reduced haloperidol in healthy volunteers. Eur J Clin Pharmacol 1989; 37: 45–8PubMedGoogle Scholar
  118. 118.
    Tyndale RF, Kalow W, Inaba T. Oxidation of reduced haloperidol to haloperidol: involvement of human P450IID6 (sparteine/debrisoquine monooxygenase). Br J Clin Pharmacol 1991; 31: 655–60PubMedGoogle Scholar
  119. 119.
    Llerena A, Alm C, Dahl M-L, et al. Haloperidol disposition is dependent on debrisoquine hydroxylation phenotype. Ther Drug Monit 1992; 14: 92–7PubMedGoogle Scholar
  120. 120.
    Llerena A, Dahl M-L, Ekqvist B, et al. Haloperidol disposition is dependent on the debrisoquine hydroxylation phenotype: increased plasma levels of the reduced metabolite in poor metabolizers. Ther Drug Monit 1992; 14: 261–4PubMedGoogle Scholar
  121. 121.
    Nyberg S, Farde L, Halldin C, et al. D2 Dopamine receptor occupancy during low-dose treatment with haloperidol decanoate. Am J Psychiatry 1995; 152: 173–8PubMedGoogle Scholar
  122. 122.
    Potkin SG, Shen Y, Pardes H, et al. Haloperidol concentrations elevated in Chinese patients. Psychiatry Res 1984; 12: 167–72PubMedGoogle Scholar
  123. 123.
    Lin KM, Poland RE, Lau JK, et al. Haloperidol and prolactin concentrations in Asians and Caucasians. J Clin Psychopharmacol 1988; 8: 195–201PubMedGoogle Scholar
  124. 124.
    Lin KM, Finder E. Neuroleptic dosage for Asians. Am J Psychiatry 1983; 140: 490–1PubMedGoogle Scholar
  125. 125.
    Wood AJJ, Zhou H. Ethnic differences in drug disposition and responsiveness. Clin Pharmacokinet 1991; 20: 350–73PubMedGoogle Scholar
  126. 126.
    Baldessarini RJ, Frankenburg ER. Clozapine: a novel antipsychotic agent. N Engl J Med 1991; 324: 746–54PubMedGoogle Scholar
  127. 127.
    Dahl M-L, Llerena A, Bondesson U, et al. Disposition of clozapine in man: lack of association with debrisoquine and S-mephenytoin hydroxylation polymorphisms. Br J Clin Pharmacol 1994; 37: 71–4PubMedGoogle Scholar
  128. 128.
    Fischer B, Vogels G, Maurer G, et al. The antipsychotic clozapine is metabolized by the polymorphic human microsomal recombinant cytochrome P4502D6. J Pharmacol Exp Ther 1992; 260: 1355–60PubMedGoogle Scholar
  129. 129.
    Jerling M, Lindström L, Bondesson U, et al. Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit 1994; 16: 368–74PubMedGoogle Scholar
  130. 130.
    Kalow W, Tang B-K. The use of caffeine for enzyme assays: a critical appraisal. Clin Pharmacol Ther 1993; 53: 503–14PubMedGoogle Scholar
  131. 131.
    Carrillo JA, Benitez J. Caffeine metabolism in a healthy Spanish population: N-acetylator phenotype and oxidation pathways. Clin Pharmacol Ther 1994; 55: 293–304PubMedGoogle Scholar
  132. 132.
    Bertilsson L, Carrillo JA, Dahl M-L, et al. Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test. Br J Clin Pharmacol 1994; 38: 471–3PubMedGoogle Scholar
  133. 133.
    Haring C, Meise U, Humpel C, et al. Dose related plasma levels of clozapine: influence of smoking behaviour, sex and age. Psychopharmacol 1989; 99: 538–40Google Scholar
  134. 134.
    Vainer JL, Chouinard G. Interaction between caffeine and clozapine. J Clin Psychopharmacol 1994; 14: 284–5PubMedGoogle Scholar
  135. 135.
    Carrillo JA, Jerling M, Bertilsson L. Comments to ‘Interaction between caffeine and clozapine’. J Clin Psychopharmacol 1995; 15: 376–7PubMedGoogle Scholar
  136. 136.
    von Bahr C, Movin G, Nordin C, et al. Plasma levels of thioridazine and metabolites are influenced by the debrisoquine hydroxylation phenotype. Clin Pharmacol Ther 1991; 49: 234–40Google Scholar
  137. 137.
    Steiner E, Movin G, Lindeberg A, et al. The elimination of remoxipride — a new dopamine D2-receptor antagonist — covaries with the ability to hydroxylate debrisoquine. 34th Nordic Meeting of Pharmacology, Toxicology and Clinical Pharmacology; 1989 Jun 26–28; ReykjavikGoogle Scholar
  138. 138.
    Huang M-L, van Peer A, Woestenborghs R, et al. Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharmacol Ther 1993; 54: 257–68PubMedGoogle Scholar
  139. 139.
    Fonne-Pfister R, Bargetzi MJ, Meyer UA. MPTP, the neurotoxin inducing Parkinson’s disease, is a potent competitive inhibitor of human and rat cytochrome P450 isozymes (P450 bufI.P450dbl) catalyzing debrisoquine 4-hydroxylation. Biochem Biophys Res Commun 1987; 148: 1144–50PubMedGoogle Scholar
  140. 140.
    Niznik HB, Tyndale RF, Sallee RF, et al. The dopamine transporter and cytochrome P450IID1 (debrisoquine 4-hydroxylase) in brain: resolution and identification of two distinct [3H] GBR-12935 binding proteins. Arch Biochem Biophys 1990; 276: 424–32PubMedGoogle Scholar
  141. 141.
    Kalow W, Tyndale RF. Debrisoquine/sparteine monooxygenase and other P450s in brain. In: Kalow W, editor. Pharmacogenetics of drug metabolism. New York: Pergamon Press, Inc., 1992: 649–56Google Scholar
  142. 142.
    Bertilsson L, Alm C, de las Carreras C, et al. Debrisoquine hydroxylation polymorphism and personality [letter]. Lancet 1989; 1: 555PubMedGoogle Scholar
  143. 143.
    Llerena A, Edman G, Cobaleda J, et al. Relationship between personality and debrisoquine hydroxylation capacity — suggestion of an endogenous neuroactive substrate or product of the cytochrome P4502D6. Acta Psychiatr Scand 1993; 87: 23–8PubMedGoogle Scholar
  144. 144.
    Brøsen K, Sindrup SH, Skjelbo E, et al. Role of genetic polymorphism in psychopharmacology — an update. In: Gram LF, Balant LP, Meltzer HY, et al., editors. Clinical pharmacology in psychiatry. Berlin, Heidelberg: Springer Verlag, 1993: 199–211Google Scholar
  145. 145.
    Bertilsson L, Henthorn TK, Sanz E, et al. Importance of genetic factors in the regulation of diazepam metabolism: relationship to S-mephenytoin, but not debrisoquine hydroxylation phenotype. Clin Pharmacol Ther 1989; 45: 348–55PubMedGoogle Scholar
  146. 146.
    Zhang Y, Reviriego J, Lou YQ, et al. Diazepam metabolism in native Chinese poor and extensive hydroxylators of S-mephenytoin: interethnic differences in comparison with white subjects. Clin Pharmacol Ther 1990; 48: 496–502PubMedGoogle Scholar
  147. 147.
    Bertilsson L, Kalow W. Why are diazepam metabolism and polymorphic S-mephenytoin hydroxylation associated with each other in white and Korean populations, but not in Chinese populations? Clin Pharmacol Ther 1993; 53: 608–10PubMedGoogle Scholar
  148. 148.
    Kalow W, Bertilsson L. Interethnic factors affecting drug activity. In: Testa B, Meyer UA, editors. Advances in drug research. Vol. 25. London: Academic Press, 1994: 1–53Google Scholar
  149. 149.
    Ghoneim MM, Korttila K, Chiang CK, et al. Diazepam effect and kinetics in Caucasians and Orientals. Clin Pharmacol Ther 1981; 29: 749–56PubMedGoogle Scholar
  150. 150.
    Kumana CR, Lauder IJ, Chan M, et al. Differences in diazepam pharmacokinetics in Chinese and white Caucasians — relation to body lipid stores. Eur J Clin Pharmacol 1987; 32: 211–5PubMedGoogle Scholar
  151. 151.
    Andersson T, Miners JO, Veronese ME, et al. Diazepam metabolism by human liver microsomes is mediated by both S-mephenytoin hydroxylase and CYP3A isoforms. Br J Clin Pharmacol 1994; 38: 131–7PubMedGoogle Scholar
  152. 152.
    Perucca E, Gatti G, Cipolla G, et al. Inhibition of diazepam metabolism by fluvoxamine: a pharmacokinetic study in normal volunteers. Clin Pharmacol Ther 1994; 56: 471–6PubMedGoogle Scholar

Copyright information

© Adis International Limited 1996

Authors and Affiliations

  • Leif Bertilsson
    • 1
  • Marja-Liisa Dahl
    • 1
  1. 1.Department of Medical Laboratory Sciences and Technology, Division of Clinical Pharmacology, Karolinska InstituteHuddinge University HospitalHuddingeSweden

Personalised recommendations