Hostname: page-component-5c6d5d7d68-wp2c8 Total loading time: 0 Render date: 2024-08-22T11:32:13.889Z Has data issue: false hasContentIssue false
  • English
  • Français

Pharmacogenetics of the hepatic cytochrome P450 enzyme system: its relevance for prescribing in psychiatry

Published online by Cambridge University Press:  13 June 2014

Alan O'Donohoe  and
Michael Gill
Alan O'Donohoe
Affiliation:
Department of Psychiatry, St. James's Hospital, James's St, Dublin 8, Ireland
Michael Gill
Affiliation:
Department of Psychiatry, St. James's Hospital, James's St, Dublin 8, Ireland
Get access Rights & Permissions [Opens in a new window]

Abstract

This article reviews the current knowledge regarding the hepatic cytochrome P450 system, with particular reference to its effect on psychotherapeutic medication. The metabolic processes – by which drugs are broken down in the liver by cytochrome P450 enzymes – are affected by genetic variation between individuals, inhibition and induction of these enzymes by other drugs, disease and age. Genetic influences and enzyme inhibition/induction are discussed in particular detail in this article.

Keywords

Cytochrome P450PharmacogeneticsPsychopharmacologyGenotypeEnzyme inhibition
Type
Review
Information
Irish Journal of Psychological Medicine , Volume 15 , Issue 3 , September 1998 , pp. 96 - 99
Copyright
Copyright © Cambridge University Press 1998

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1.Nelson, DR, Strobel, HW. Mol Biol Evol 1987; 4: 527–93.Google Scholar
2.Nebert, DW, Nelson, DR, Adesnik, M. The P450 superfamily: updated list of all genes and recommended nomenclattire for the chromosomal loci. DNA Seq 1989; 8: 1–13.CrossRefGoogle ScholarPubMed
3.Nebert, DW, Nelson, DR, Coon, MJet al.The P450 superfamily: update on new sequences, gene mapping and recommended nomenclature. DNA Cell Biol 1991; 10: 1–14.CrossRefGoogle ScholarPubMed
4.Nelson, DR, Kamataki, T, Waxman, DJet al.The P450 superfamily, update on new sequences, gene mapping, accessor numbers, early trivial names of enzymes and nomenclature. DNA Cell Biol 1993; 12: 1–51.CrossRefGoogle Scholar
5.Nelson, DR, Koymans, L, Kamataki, Tet al.P450 superfamily-update on new sequences gene mapping, accession numbers and nomenclature. Pharmacogenetics 1996: 6: 1.CrossRefGoogle Scholar
6.Guengerich, FP, Muller-Enoch, D, Blair, IA. Oxidation of quinidine by human liver cytochrome P450. Moi Pharmacol 1986; 30: 287–95.Google Scholar
7.Vogel, F, Motulsky, AG. Human genetics, problems and approaches. Springer-Verlag, Berlin, Heidelberg, New York: 1982.Google Scholar
8.Lledo, P, Abrams, SM, Johnston, A, Patel, M, Pearson, RM, Turner, P. The influence of debrisoquine hydroxylase phenotype on the pharmacokinetics of mexiletine. Eur J Clin Pharmacol 1993: 44: 63–7.CrossRefGoogle Scholar
9.Lindsay De, Vane C. Pharmacogenetics and drug metabolism of newer antidepressant agents. J Clin Psychiatry 1994; 55(12): 38–45.Google Scholar
10.Eichelbaum, M. Ein neuendeckter defekt im Arzneimirtelstoffwechsel den Menschen: Die fehlende N-oxydation des Spartein. Habilitationsschrift. Medical Faculty of Bonn 1975: 1–94.Google Scholar
11.Mahgoub, A, Idle, JR, Dring, LG. Polymorphic hydroxylation of debrisoquine in man. Lancet 1977; ii: 584–6.CrossRefGoogle Scholar
12.Bertillson, LA, Dengler, HJ, Eichelbaum, M. Pharmacogenetic co-variation of defective N-oxidation of sparteine and 4-hydroxylation of debrisoquine. Eur J Clin Pharmacol 1980; 17: 153–5.CrossRefGoogle Scholar
13.Kroemer, HK, Eichelbaum, M. ‘Its the genes, stupid’. Molecular bases and clinical consequences of genetic cytochrome P4502D6 polymorphism. Life Sci 1995; 56: 2285–98.Google ScholarPubMed
14.Bertilsson, L, Eichelbaum, M, Mellstrom, B. Nortriptyline and antipyrine clearance in relation to debrisoquine hydroxylation in man. Life Sci 1980; 27: 1673–7.CrossRefGoogle ScholarPubMed
15.Mellstrom, B, Bertilsson, L, Salve, J. 10-hydroxylation of nortriptyline relationship to polymorphic debrisoquine. Clin Pharmacol Ther 1981; 30:189–93.CrossRefGoogle ScholarPubMed
16.Wilkinson, GR, Guengerich, FP, Branch, RA. Genetic polymorphism of S-mephenytoin hydroxylation. Pharmacol Ther 1989; 43: 53–76.CrossRefGoogle ScholarPubMed
17.Pollock, BG, Perel, JM, Kirschner, M, Altieri, LP, Yeager, AL, Reynolds, CES-mephenytoin 4-hydroxylation in older Americans. Eur J Clin Pharmacol 1991 40: 609–11.CrossRefGoogle ScholarPubMed
18.Skjelbo, E, Brosen, K, Hallas, J, Gram, LF. The mephenytoin oxidation polymorphism is partially responsible for the N-demethylation of imipramine. Clin Pharmacol Ther 1991; 49: 18–23.CrossRefGoogle ScholarPubMed
19.Sindrup, SH, Brosen, K, Hansen, MGJ, Aaes-Jorgenson, T, Overo, KF, Gram, LF. Pharmacokinetics of citalopram in relation to the sparteine and S-mephenytoin oxidation polymorphism. Ther Drug Monit 1993; 13: 11–7.CrossRefGoogle Scholar
20.Bertillson, L, Henthorn, TK, Sanz, E. Importance of genetic factors in the regulation of diazepam metabolism: relationship to S-mephenytoin, but not debrisoquine, hydroxylation phenotype. Clin Pharmacol Ther 1989; 45: 348–55.CrossRefGoogle Scholar
21.Campbell, ME, Grant, DM. Biotransformation of caffeine, perxanthine, theophylline and theobromine by polycyclic aromatic hydrocarbon inducible cytochrome P450 in human liver microsomes. Drug Metab Dispos Biol Fate Chem 1987; 15: 237–48.Google ScholarPubMed
22.Jerling, M, Lindstrom, L, Bondesson, U, Bertillson, L. Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence for a therapeutic drug monitoring service. Ther Drug Monit 1994; 16: 368–74.CrossRefGoogle Scholar
23.Alexanderson, B, Evans, DAP, Sjoqvist, F. Steady state plasma levels of nortriptyline in twins: influence of genetic factors and drug therapy. BMJ 1969; 4: 764–8.CrossRefGoogle ScholarPubMed
24.Asberg, M, Sjoqvist, F. Therapeutic monitoring of tricyclic antidepressants – clinical aspects. In: Marks, Richens, eds. Therapeutic Drug Monitoring. Edinburgh, UK: Churchill Livingstone, 1981: 224–38.Google Scholar
25.Preskorn, SH. Pharmacokinetics of antidepressants: why and how they are relevant to treatment. J Clin Psychiatry 1993; 54(9): 14–34.Google ScholarPubMed
26.Bertilsson, L, Mellstrom, B, Sjoqvist, F. Slow hydroxylation of nortriptyline and concomitant poor debrisoquine hydroxylase-clinical implications. Lancet 1981: 560–1.Google Scholar
27.Balant-Gorgia, AL, Balant, LP, Garrone, G. High blood concentrations of imipramine or clomipramine, and therapeutic failure: a case report study using drug monitoring data. Ther Drug Monitoring 1989; 11: 415–20.CrossRefGoogle ScholarPubMed
28.Bertillson, L, Asberg-Wistedt, A, Gustaffson, LL. Extremely rapid hydroxylation of debrisoquine: a case report with implications for treatment with nortriptyline and other tricyclic antidepressants. Ther Drug Monitoring 1985; 7: 478–80.CrossRefGoogle Scholar
29.Sindrup, SH, Brosen, K, Gram, LFet al.The relationship between paroxetine and the sparteine oxidation polymorphism. Clin Pharmacol Ther 1992; 51: 278–87.CrossRefGoogle ScholarPubMed
30.Crewe, HK, Lennard, MS, Tucker, GT, Woods, FR, Haddock, RE. The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol 1992; 34: 262–5.CrossRefGoogle ScholarPubMed
31.Brosen, K, Skjelbo, E. Fluoxetine and norfluoxetine are potent inhibitors of P4502D6: the source of the sparteine/debrisoquine oxidation polymorphism (letter). Br J Clin Pharmacol 1991; 32: 136–7.CrossRefGoogle Scholar
32.Ciraulo, DA, Shader, RI. Fluoxetine drug-drug interactions: antidepressants and antipsychotics. J Clin Psychopharmacol 1990; 10: 48–50.CrossRefGoogle ScholarPubMed
33.Vandel, S, Bertschy, G, Bonin, B. Tricyclic antidepressant plasma levels after fluoxetine addition. Neuropsychobiology. 1992; 25: 205–7.CrossRefGoogle ScholarPubMed
34.Lemberger, L, Rowe, H, Bosomworth, JC. The effect of fluoxetine on pharmacokinetics and psychomotor responses of diazepam. Clin Pharmcol Ther 1988; 43: 412–9.CrossRefGoogle ScholarPubMed
35.Nightingale, SL. Fluoxetine labelling revised to identify phenytoin interactions and to recommend against use in nursing mothers (letter). JAMA 1994; 271: 1067.CrossRefGoogle Scholar
36.Shader, RJ, Greenblatt, DJ, von, Molthe U. Fluoxetine inhibition of phenytoin metabolism. J Clin Psychopharmacol 1994; 14: 375–6.CrossRefGoogle ScholarPubMed
37.Brosen, K, Skjelbo, E, Rasmussen, BB, Poulsen, HE, Loft, S. Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol 1993; 45: 1211–14.CrossRefGoogle ScholarPubMed
38.Bertschy, G, Vandel, S, Vandel, B, Allers, G, Volmat, R. Fluvoxamme-TCA interactions: an accidental finding (letter). Eur J Clin Pharmacol 1991; 40: 119–20.CrossRefGoogle Scholar
39.Hiemke, C, Weigman, K, Hartter, S, Dahmen, N, Wetzel, H, Muller, H. Elevated levels of clozapine in serum after addition of fluvoxamine. J Clin Psychopharmacol 1994; 14: 279–81.CrossRefGoogle ScholarPubMed
40.Daniel, DG, Randolph, C, Jaskin, G. Co-administration of fluvoxamine increases serum concentrations of haloperidol. J Clin Psychopharmacol 1994; 14: 340–3.CrossRefGoogle Scholar
41.Lydiard, RB, Anton, RF, Cunningham, T. Interactions between sertraline and tricyclic antidepressants (letter). Am J Psychiatry 1993; 150: 1125–6.Google Scholar
42.Barros, J, Asnis, G. An interaction of sertraline and desipramine (letter). Am J Psychiatry 1993; 150: 1751.Google Scholar
43.Green, DS, Dockens, RC, Salazar, DE. Coadministration of nefadozone and benzodiazepines 1: pharmacokinetic assessment (abstract). Clin Pharmacol Ther 1994; 55: 141.Google Scholar
44.Axelsson, R, Martennson, E. Curr Ther Res 1977; 21: 587–605.Google Scholar
45.Von Bohr, C. Clin Pharmacol Ther 1991; 49: 34–240.Google Scholar
46.Llerena, A, Aim, C, Dahl, M-L, Ekqvist, B, Bertillson, L. Haloperidol disposition is dependent on debrisoquine hydroxylation phenotype. Ther Drug Monit 1990; 14: 92–7.CrossRefGoogle Scholar
47.Jerling, M, Dahl, M-L, Aberg-Wistedt, A, Liljenberg, B, Lindell, NE, Bertilson, L. The CYP2D6 genotype predicts the oral clearance of the neuroleptic agents perphenazine and zuclopenthixol. Clin Pharmacol Ther 1996; 59(4) 423–8.CrossRefGoogle ScholarPubMed
48.Arranz, MJ, Dawson, E, Sheikh, Set al.Cytochrome P4502D6 genotype does determine response to clozapine. Br J Clin Pharmacol 1995; 39(4): 417–20.CrossRefGoogle ScholarPubMed
49.Pollock, BG, Mulsant, BH, Sweet, RA. Prospective cytochrome P450 phenotyping for neuroleptic treatment in dementia. Psychopharmacol Bull 1995; 31(2): 327–31.Google ScholarPubMed
50.Bertilsson, L, Dahl, M-L, Sjoqvist, Fet al.Molecular basis for rational megaprescibing in ultrarapid bydroxylators of debrisoquine. Lancet 1993: 341–6.CrossRefGoogle ScholarPubMed
51.Hall, MC, Gregory, WL, Idle, IR. Pharmacogenetics: can the therapeutic key objective be accomplished?Horizons in Medicine. In press.Google Scholar