Clinical Pharmacokinetics

, Volume 32, Supplement 1, pp 1–21 | Cite as

Clinically Relevant Pharmacology of Selective Serotonin Reuptake Inhibitors

An Overview with Emphasis on Pharmacokinetics and Effects on Oxidative Drug Metabolism
  • Sheldon H. Preskorn


This paper presents an overview of the clinically relevant pharmacology of selective serotonin reuptake inhibitors (SSRIs) with an emphasis on their pharmacokinetics and effects on cytochrome P450 (CYP) enzymes. The SSRIs are potent inhibitors of the neuronal reuptake pump for serotonin (5-hydroxytryptamine; 5-HT) and have minimal effects on a number of other sites of actions (e.g. neuroreceptors and fast sodium channels). For this reason, drugs in this class have remarkable similarity as regards acute and maintenance antidepressant efficacy and tolerability profile.

However, individual members of this class differ substantially in their pharmacokinetics and effects on CYP enzymes. Most SSRIs have a half-life (t½) of approximately 1 day. Fluoxetine, however, has a longer t½ of 2 to 4 days, and its active metabolite, norfluoxetine, has an extended t½ of 7 to 15 days. Fluoxetine, paroxetine and, to a lesser extent, fluvoxamine inhibit their own metabolism. That is not the case for citalopram or sertraline.

There are nonlinear increases in paroxetine plasma concentrations with dosage increases, but proportional changes with citalopram and sertraline. Indirect data suggest that fluoxetine and fluvoxamine also have nonlinear pharmacokinetics over their usual dosage range. Age-related increases in plasma drug concentrations for citalopram (≈130%) and paroxetine (≈50 to 100%) have been observed in healthy elderly (65 to 75 years) persons versus those who are younger. There is an age-gender interaction for sertraline, with its plasma concentrations being 35 to 40% lower in young men than in elderly or young females or elderly males. While there is no apparent change in fluvoxamine plasma levels as a function of age, plasma drug concentrations are 40 to 50% lower in males than in females. Limited data from clinical trials suggest that age-related differences with fluoxetine may be comparable to those of citalopram and paroxetine.

Marked differences exist between the SSRIs with regard to effects on specific CYP enzymes and, thus, the likelihood of clinically important pharmacokinetic drug-drug interactions. The most extensive in vitro and in vivo research has been done with fluoxetine, fluvoxamine and sertraline; there has been less with paroxetine and citalopram. The available in vivo data at each drug’s usually effective antidepressant dose are summarised below. Citalopram produces mild inhibition of CYP2D6. Fluvoxamine produces inhibition (which would be expected to be clinically meaningful) of two CYP enzymes, CYP1A2 and CYP2C19, and probably a third, CYP3A3/4. Fluoxetine substantially inhibits CYP2D6 and probably CYP2C9/10, moderately inhibits CYP2C19 and mildly inhibits CYP3A3/4. Paroxetine substantially inhibits CYP2D6 but does not appear to inhibit any other CYP enzyme. Sertraline produces mild inhibition of CYP2D6 but has little, if any, effect on CYP1A2, CYP2C9/10, CYP2C19 or CYP3A3/4. Understanding the similarities and differences in the pharmacology of SSRIs can aid the clinician in optimal use of this important class of anti-depressants.


Adis International Limited Fluoxetine Paroxetine Sertraline Selective Serotonin Reuptake Inhibitor 
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  1. 1.
    Montgomery SA, Dufour H, Brion S, et al. The prophylactic efficacy of fluoxetine in unipolar depression. Br J Psychiatry 1988; 153 Suppl. 3: 69–76Google Scholar
  2. 2.
    Eric LA. A prospective double-blind comparative multicentre study of paroxetine and placebo in preventing recurrent major depression episodes. Biol Psychiatry 1991; 29 Suppl. 11: 254S–255SGoogle Scholar
  3. 3.
    Doogan DP, Caillard V. Sertraline in the prevention of depression. Br J Psychiatry 1992; 160: 217–22PubMedCrossRefGoogle Scholar
  4. 4.
    Preskorn S. The clinically relevant pharmacology of selective serotonin reuptake inhibitors. Caddo, Oklahoma: Professional Communications Inc., 1996Google Scholar
  5. 5.
    Preskorn S. Comparison of the tolerability of buproprion, fluoxetine, imipramine, nefazodone, paroxetine, sertraline, and venlafaxine. J Clin Psychiatry 1995; 56 Suppl. 6: 12–21PubMedGoogle Scholar
  6. 6.
    Preskorn S. Targeted pharmacotherapy in depression management: comparative pharmacokinetics of fluoxetine, paroxetne and sertraline. Int Clin Psychopharmacol 1994; 9 Suppl. 3: 13–9PubMedCrossRefGoogle Scholar
  7. 7.
    Van Harten J. Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clin Pharmacol 1993; 24(3): 203–20CrossRefGoogle Scholar
  8. 8.
    Goodnick PJ. Pharmacokinetic optimisation of therapy with newer antidepressants. Clin Pharmacokinet 1994; 27: 307–30PubMedCrossRefGoogle Scholar
  9. 9.
    Lane R, Baldwin D, Preskorn S. The SSRIs: advantages, disadvantages and differences. J Psychopharmacol 1995; 9(2) Suppl.: 163–78PubMedGoogle Scholar
  10. 10.
    Janicak PPG, Davis J, Preskorn SH, et al. Principles and practice of psychopharmacotherapy. Baltimore: Williams & Wilkins, 1994Google Scholar
  11. 11.
    Marsden C, Tyrer P, Casey P, et al. Changes in human whole blood 5-hydroxytryptamine (5-HT) and platelet 5-HT uptake during treatment with paroxetine, a selective 5-HT uptake inhibitor. J Psychopharmacol 1987; 1: 244–50PubMedCrossRefGoogle Scholar
  12. 12.
    Wernicke JF, Dunlop SR, Dornseif BE, et al. Fixed dose fluoxetine therapy for depression. Psychopharmacol Bull 1987; 23: 164–8PubMedGoogle Scholar
  13. 13.
    Wernicke JF, Dunlop SR, Dornseif BE, et al. Low dose fluoxetine therapy for depression. Psychopharmacol Bull 1988; 24: 183–8PubMedGoogle Scholar
  14. 14.
    Dunner DL, Dunbar GC. Optimal dose regimen for paroxetine. J Clin Psychiatry 1992; 53 Suppl. 2: 21–6PubMedGoogle Scholar
  15. 15.
    Fabre LF, Abuzzahab FS, Amin M, et al. Sertraline safety and efficacy in major depression: a double-blind fixed dose comparison with placebo. Biol Psychiatry 1995; 38: 592–602PubMedCrossRefGoogle Scholar
  16. 16.
    Bjerkenstedt L, Flyckt L, Overo KF, et al. Relationship between clinical effects, serum drug concentration and serotonin uptake inhibition in depressed patients treated with citalopram. Eur J Clin Pharmacol 1985; 28: 553–7PubMedCrossRefGoogle Scholar
  17. 17.
    Dufour H, Bouchacourt M, Thermoz P, et al. Citalopram — a highly selective 5-HT reuptake inhibitor — in the treatment of depressed patients. Int Clin Psycopharmacol 1987; 2: 225–37CrossRefGoogle Scholar
  18. 18.
    Preskorn SH, Silkey B, Beber J, et al. Antidepressant response and plasma concentrations of fluoxetine. Ann Clin Psychiatry 1991; 3: 147–51CrossRefGoogle Scholar
  19. 19.
    Kelly MW, Perry PJ, Holstad SG, et al. Serum fluoxetine and norfluoxetine concentrations and antidepressant response. Ther Drug Monit 1989; 11: 165–70PubMedCrossRefGoogle Scholar
  20. 20.
    Bouquet S, Vandel S, Bertschy S, et al. Pharmacokinetics of fluoxetine and fluvoxamine in depressed patients: personal results. Clin Neuropharmacol 1992; 15 Suppl. 1: 82A-83ACrossRefGoogle Scholar
  21. 21.
    Kasper S, Dotsch M, Vieira A, et al. Plasma concentration of fluvoxamine and maprotiline in major depression: implications on therapeutic efficacy and side effects. Eur Neuropsychopharmacol 1993; 3: 13–21PubMedCrossRefGoogle Scholar
  22. 22.
    Laursen AL, Mikkelsen PL, Rasmussen S, et al. Paroxetine in the treatment of depression — a randomized comparison with amitriptyline. Acta Psychiatr Scand 1985; 71: 249–55PubMedCrossRefGoogle Scholar
  23. 23.
    Tasker TCG, Kaye CM, Zussman Bd, et al. Paroxetine plasma levels: lack of correlation with efficacy or adverse events. Acta Psychiatr Scand 1989; 80 Suppl. 350: 152–5CrossRefGoogle Scholar
  24. 24.
    Preskorn SH, Harvey A. Biochemical and clinical dose-response curves with sertraline. Clin Pharmacol Ther 1996; 59: 180CrossRefGoogle Scholar
  25. 25.
    Lemberger L, Bergstrom RF, Wolen RL, et al. Fluoxetine: clinical pharmacology and physiologic disposition. J Clin Psychiatry 1985; 46 (3 Pt 2): 14–9PubMedGoogle Scholar
  26. 26.
    Wood K, Swade C, Abou-Saleh M, et al. Drug plasma levels and platelet 5-HT uptake inhibition during long-term treatment with fluvoxamine or lithium in patients with affective disorders. Br J Clin Pharmacol 1983; 15 Suppl. 3: 365S–368SPubMedCrossRefGoogle Scholar
  27. 27.
    Wong DT, Fuller RW, Robertson DW. Fluoxetine and its two enantiomers as selective serotonin uptake inhibitors. Acta Pharm Nord 1990; 2: 171–80PubMedGoogle Scholar
  28. 28.
    Wong DT, Bymaster FP, Reid LR, et al. Norfluoxetine enantiomers as inhibitors of serotonin uptake in rat brain. Neuropsychopharmacology 1993; 8: 337–44PubMedGoogle Scholar
  29. 29.
    Fuller RW, Snoddy HD, Krushinski JH, et al. Comparison of norfluoxetine enantiomers as serotonin uptake inhibitors in vivo. Neuropharmacology 1992; 31: 997–1000PubMedCrossRefGoogle Scholar
  30. 30.
    Norman TR, Gupta RK, Burrows GD, et al. Relationship between antidepressant response and plasma concentrations of fluoxetine and norfluoxetine. Int Clin Psychopharmacol 1993; 8: 25–9PubMedCrossRefGoogle Scholar
  31. 31.
    Stevens JC, Wrighton SA. Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P 450. J Pharmacol Exp Ther 1993; 266(2): 964–71PubMedGoogle Scholar
  32. 32.
    Hyttel J, Bøgesø KP, Perregard J, et al. The pharmacological effect of citalopram resides in the S-(+)- enantiomer. J Neural Transmission 1992; 88: 157–60CrossRefGoogle Scholar
  33. 33.
    Rochat B, Amey M, Baumann P. Analysis of enantiomers of citalopram and its demethylated metabolites in plasma of depressive patients using chiral reverse-phase liquid chromatography. Ther Drug Monit 1995; 17: 273–9PubMedCrossRefGoogle Scholar
  34. 34.
    Baumann P, Rochat B. Comparative pharmacokinetics of selective serotonin reuptake inhibitors: a look behind the mirror. Int Clin Psychopharmacol 1995; 10 Suppl. 1: 15–21PubMedCrossRefGoogle Scholar
  35. 35.
    Preskorn SH. Pharmacokinetics of antidepressants: why and how they are relevant to treatment. J Clin Psychiatry 1993; 54 Suppl. 9: 14–34PubMedGoogle Scholar
  36. 36.
    Brøsen K, Skjelbo E, Rasmussen BB, et al. Fluvoxamine is a potent inhibitor of cytochrome P4501A 2. Biochem Pharmacol 1993; 45(6): 1211–4PubMedCrossRefGoogle Scholar
  37. 37.
    Rasmussen BB, Maenpaa J, Pelkonen O, et al. Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine. Br J Clin Pharmacol 1995; 39: 151–9PubMedCrossRefGoogle Scholar
  38. 38.
    von Moltke LL, Greenblatt DJ, Duan SX, et al. In vitro biotransformation of phenacetin to acetaminophen: metabolic inhibition by antidepressants. Am Soc Clin Pharmacol Ther 1996; 59: 175CrossRefGoogle Scholar
  39. 39.
    Crewe HK, Lennard MS, Tucker GT, et al. The effect of selective serotonin reuptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol 1992; 34: 262–5PubMedCrossRefGoogle Scholar
  40. 40.
    Skjelbo E, Brøsen K. Inhibitors of imipramine metabolism by human liver microsomes. Br J Clin Pharmacol 1992; 34: 256–61PubMedCrossRefGoogle Scholar
  41. 41.
    von Moltke LL, Greenblatt DJ, Court MH, et al. Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. J Clin Psychopharmacol 1995; 15: 125–31CrossRefGoogle Scholar
  42. 42.
    Otton SV, Ball SE, Cheung SW, et al. Comparative inhibition of the polymorphic enzymes CYP2D6 by venlafaxine (VF) and other 5HT uptake inhibitors. Clin Pharmacol Ther 1994; 55(2): 141Google Scholar
  43. 43.
    Otton SV, Wu D, Joffe RT, et al. Inhibition by fluoxetine of cytochrome P450 2D6 activity. Clin Pharmacol Ther 1993; 53: 401–9PubMedCrossRefGoogle Scholar
  44. 44.
    von Moltke L, Greenblatt D, Cotreau-Bibbo M, et al. Inhibitors of alprazolam metabolism in vitro: effect of serotoninreuptake-inhibitor antidepressants, ketoconazole and quinidine. Br J Clin Pharmacol 1994; 38: 23–31CrossRefGoogle Scholar
  45. 45.
    Sindrup SH, Brøsen K, Hansen MG, et al. Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms. Ther Drug Monit 1993; 15: 11–7PubMedCrossRefGoogle Scholar
  46. 46.
    Goldstein JA, de Morais SM. Biochemistry and molecular biology of the human CYP 2C subfamily. Pharmacogenetics 1994; 4: 285–99PubMedCrossRefGoogle Scholar
  47. 47.
    Kupfer A, Preisig R. Pharmacogenetics of p-mephenytoin: a new drug hydroxylation polymorphism in man. Eur J Clin Pharmacol 1984; 26: 753–9PubMedCrossRefGoogle Scholar
  48. 48.
    Overmars H, Scherpenisse PM, Post LC. Fluvoxamine maleate: metabolism in man. Eur J Drug Metab Pharmacokinet 1983; 8: 269–80PubMedCrossRefGoogle Scholar
  49. 49.
    de Vries MH, Raghoebar M, Mathlener IS, et al. Single and multiple oral dose oral fluvoxamine kinetics in young and elderly subjects. Ther Drug Monit 1992; 14: 493–8PubMedCrossRefGoogle Scholar
  50. 50.
    Van Harten J, Stevens LA, Raghoebar M, et al. Fluvoxamine does not interact with alcohol or potentiate alcohol-related impairment of cognitive function. Clin Pharmacol Ther 1992; 52: 427–35PubMedCrossRefGoogle Scholar
  51. 51.
    Bergstrom RF, Lemberger L, Farid NA, et al. Clinical pharmacology and pharmacokinetics of fluoxetine: a review. Br J Psychiatry 1988; 153 Suppl. 3: 47–50Google Scholar
  52. 52.
    Bergstrom RF, Peyton AL, Lemberger L. Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther 1992; 51: 239–48PubMedCrossRefGoogle Scholar
  53. 53.
    Altamura AC, Moro AR, Percudani M. Clinical pharmacokinetics of fluoxetine. Clin Pharmacokinet 1994; 26: 201–14PubMedCrossRefGoogle Scholar
  54. 54.
    Hamelin BA, Turgeon J, Vallie F, et al. Genetic determinate of sertraline and fluoxetine disposition in twenty healthy volunteers. Canadian Society of Clinical Pharmacology Meeting, Sept 1995Google Scholar
  55. 55.
    Otton SV, Wu D, Joffe RT, et al. Inhibition by fluoxetine of cytochrome P450 2D6 activity. Clin Pharmacol Ther 1993; 53: 401–9PubMedCrossRefGoogle Scholar
  56. 56.
    Baumann P, Bertschy G. Pharmacodynamic and pharmacokinetic interactions of selective serotonin re-uptake inhibiting antidepressants (SSRIs) with other psychotropic drugs. Nord J Psychiatry 1993; 47 Suppl. 30: 13–9CrossRefGoogle Scholar
  57. 57.
    Bolden-Watson C, Richelson E. Blockade by newly-developed antidepressants of biogenic amine uptake into rat brain synaptosomes. Life Sci 1993; 52: 1023–9PubMedCrossRefGoogle Scholar
  58. 58.
    Hyttel J. Comparative pharmacology of selective serotonin reuptake inhibitors (SSRIs). Nord J Psychiatry 1993; 47 Suppl. 3: 5–12CrossRefGoogle Scholar
  59. 59.
    Preskorn S, Alderman J, Chung M, et al. Pharmacokinetics of desipramine coadministered with sertraline or fluoxetine. J Clin Psychopharmacol 1994; 14(2): 90–8PubMedCrossRefGoogle Scholar
  60. 60.
    Greenblatt DJ, Preskorn SH, Cotreau MM, et al. Fluoxetine impairs clearance of alprazolam but not of clonazepam. Clin Pharmacol Ther 1992; 52: 479–86PubMedCrossRefGoogle Scholar
  61. 61.
    Sindrup SH, Brøsen K, Gram LF, et al. The relationship between paroxetine and the sparteine oxidation polymorphism. Clin Pharmacol Ther 1992; 51: 278–87PubMedCrossRefGoogle Scholar
  62. 62.
    Bloomer JC, Woods FR, Haddock RE, et al. The role of cytochrome P4502D6 in the metabolism of paroxetine by human liver microsomes. Br J Clin Pharmacol 1992; 33: 521–3PubMedCrossRefGoogle Scholar
  63. 63.
    Sindrup SH, Brøsen K, Gram LF. Pharmacokinetics of the selective serotonin reuptake inhibitor paroxetine: nonlinearity and relation to the sparteine oxidation polymorphism. Clin Pharmacol Ther 1992; 51: 288–95PubMedCrossRefGoogle Scholar
  64. 64.
    Greb WH, Buscher G, Dierdorf HD, et al. The effect of liver enzyme inhibition by cimetidine and enzyme induction by phenobarbitone on the pharmacokinetics of paroxetine. Acta Psychiatr Scand 1989; 80 Suppl. 350: 95–8CrossRefGoogle Scholar
  65. 65.
    Bannister SJ, Houser VP, Hulse JD, et al. Evaluation of the potential for interactions of paroxetine with diazepam, cimetidine, warfarin, and digoxin. Acta Psychiatr Scand 1989; 80 Suppl. 350: 102–6CrossRefGoogle Scholar
  66. 66.
    Andersen BB, Mikkelsen M, Vesterager A, et al. No influence of the antidepressant paroxetine on carbamazepine, valproate and phenytoin. Epilepsy Res 1991; 10: 201–4PubMedCrossRefGoogle Scholar
  67. 67.
    Alderman J, Preskorn S, Greenblatt D, et al. Desipramine pharmacokinetics when coadministered with paroxetine or sertraline. J Clin Psychopharmacol. In pressGoogle Scholar
  68. 68.
    Kaye CM, Haddock RE, Langley PF, et al. A review of the metabolism of paroxetine in man. Acta Psychiatr Scand 1989; 80 Suppl. 350: 60–75CrossRefGoogle Scholar
  69. 69.
    Demolis JL, Angeband P, Grangé JD, et al. Comparison of pharmacokinetics of orally administered sertraline in patients with stable chronic hepatic insufficiency and in healthy subjects. Presented at the French Association of Pharmacologists, Lille, France, 6–8 Oct, 1993Google Scholar
  70. 70.
    Fredericson OK, Toft B, Christophersen L, et al. Kinetics of citalopram in elderly patients. Psychopharmacol 1985; 86: 253–7CrossRefGoogle Scholar
  71. 71.
    Raghoebar M, Roseboom H. Kinetics of fluvoxamine in special populations. Poster presented at symposium on variability in pharmacokinetics and drug response. Gothenburg, October 3–5: 1988Google Scholar
  72. 72.
    Wilde MI, Plosker GL, Benfield P. Fluvoxamine. An update review of its pharmacology, and therapeutic use in depressive illness. Drugs 1993; 46: 895–924PubMedCrossRefGoogle Scholar
  73. 73.
    Feighner JP, Cohn JB. Double-blind comparative trials of fluoxetine and doxepin in geriatric patients with major depressive disorder. J Clin Psychiatry 1985; 46: 20–5PubMedGoogle Scholar
  74. 74.
    Preskorn SH. Recent pharmacologic advances in antidepressant therapy for the elderly. Am J Med 1993; 94 Suppl. 5A: 2S–12SPubMedGoogle Scholar
  75. 75.
    Hartter S, Wetzel H, Hammes E, et al. Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine in depressed patients. Psychopharmacology 1993; 110: 302–8PubMedCrossRefGoogle Scholar
  76. 76.
    Ronfeld RA, Tremaine LM, Wilner KD. Pharmacokinetics of sertraline and its N-demethyl metabolite in elderly and young male and female volunteers. Clin Pharmacokinet 1997; 32 Suppl. 1:22–30PubMedCrossRefGoogle Scholar
  77. 77.
    Harvey AT, Preskorn SH. Interactions of serotonin reuptake inhibitors with tricyclic antidepressants. Arch Gen Psychiatry 1995; 52: 783–4PubMedCrossRefGoogle Scholar
  78. 78.
    Balant LP. Pharmacokinetics in special populations. Presented at the European Psychopharmacology Consensus Meeting as a satellite meeting to the First International Congress on Hormones, Brain and Neuropsychopharmacology; Rhodes, Greece: Sep 13–17, 1993Google Scholar
  79. 79.
    Schenker S, Bergstrom RF, Wolen RL, et al. Fluoxetine disposition and elimination in cirrhosis. Clin Pharmacol Ther 1988; 44: 353–9PubMedCrossRefGoogle Scholar
  80. 80.
    Dalhoff K, Almdal TP, Bjerrum K, et al. Paroxetine in patients with cirrhosis. Psychopharmacol 1991; 103: B13Google Scholar
  81. 81.
    Warrington SJ. Clinical implications of the pharmacology of sertraline. Int Clin Psychopharmacol 1991; 6 Suppl. 2: 11–21PubMedCrossRefGoogle Scholar
  82. 82.
    Schneker S, Bergstrom RF, Wolen RL, et al. Fluoxetine disposition and elimination in cirrhosis. Clin Pharmacol Ther 1988; 44: 353–9CrossRefGoogle Scholar
  83. 83.
    Dalhoff K, Almdal TP, Pjerrum K, et al. Pharmacokinetics of paroxetine in patients with cirrhosis. Eur J Clin Pharmacol 1991; 41: 351–4PubMedCrossRefGoogle Scholar
  84. 84.
    Doyle GD, Laher M, Kelly JG, et al. The pharmacokinetics of paroxetine in renal impairment. Acta Psychiatr Scand 1989; 350 Suppl.: 89–90CrossRefGoogle Scholar
  85. 85.
    Arnoff GR, Bergstrom RF, Pottratz ST, et al. Fluoxetine kinetics and protein binding in normal and impaired renal function. Clin Pharmacol Ther 1984; 36: 138–44CrossRefGoogle Scholar
  86. 86.
    Fredericson OK. Preliminary studies of the kinetics of citalopram in man. Eur J Clin Pharmacol 1978; 14: 69–73CrossRefGoogle Scholar
  87. 87.
    Palmer KJ, Benfield P. Fluvoxamine: an overview of its pharmacological properties and review of its potential in nondepressive disorders. CNS Drugs 1994; 1: 57–87CrossRefGoogle Scholar
  88. 88.
    Nebert DW. Proposed role of drug-metabolizing enzymes: regulation of steady state levels of the ligands that affect growth, homeostasis, differentiation, and neuroendocrine functions. Mol Endocrinol 1991; 5(9): 1203–14PubMedCrossRefGoogle Scholar
  89. 89.
    Nelson DR, Kamataki T, Waxman DJ, et al. The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol 1993; 12: 1–51PubMedCrossRefGoogle Scholar
  90. 90.
    Shimada T, Yamazaki H, Mimura M, et al. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994; 270: 414–23PubMedGoogle Scholar
  91. 91.
    Gonzalez FJ. Human cytochrome p450: problems and prospects. Trends Pharmacol 1992; 13: 346–52CrossRefGoogle Scholar
  92. 92.
    Brøsen K. Isozyme specific drug oxidation: genetic polymorphism and drug-drug interactions. Nord J Psychiatry 1993; 47 Suppl. 30: 21–6CrossRefGoogle Scholar
  93. 93.
    Harvey AT, Preskorn SH. Cytochrome P450 enzymes: interpretation of their interactions with SSRIs. Pt I. J Clin Psychopharmacol 1996; 16: 273–85PubMedCrossRefGoogle Scholar
  94. 94.
    Harvey AT, Preskorn SH. Cytochrome P450 enzymes: interpretation of their interactions with SSRIs. Pt H. J Clin Psychopharmacol 1996; 16(5): 345–55PubMedCrossRefGoogle Scholar
  95. 95.
    Ketter TA, Flockhart DA, Post RM, et al. The emerging role of cytochrome P450 in psychopharmacology. J Clin Psychopharmacol 1995; 15: 387–98PubMedCrossRefGoogle Scholar
  96. 96.
    Fleishaker JC, Hulst LK. A pharmacokinetic and pharmacodynamic evaluation of the combined administration of alprazolam and fluvoxamine. Eur J Clin Pharmacol 1994; 46: 35–9PubMedCrossRefGoogle Scholar
  97. 97.
    Lasher TA, Fleishaker JC, Steenwyk RC, et al. Pharmacokinetic pharmacodynamic evaluation of the combined administration of alprazolam and fluoxetine. Psychopharmacology 1991; 104: 323–7PubMedCrossRefGoogle Scholar
  98. 98.
    Kerr BM, Thummel KE, Wurden CJ, et al. Human liver carbamazepine metabolism. Role of CYP 3A4 and CYP 2C8 in 10,11-epoxide formation. Biochem Pharmacol 1994; 47: 1969–79PubMedCrossRefGoogle Scholar
  99. 99.
    Miles MV, Tennison MB. Erythromycin effects on multipledose carbamazepine kinetics. Ther Drug Monit 1989; 11: 47–52PubMedCrossRefGoogle Scholar
  100. 100.
    Gernaat HBPE, Van De Woude J, Touw DJ. Fluoxetine and parkinsonism in patients taking carbamazepine. Am J Psychiatry 1991; 148: 1604–5PubMedGoogle Scholar
  101. 101.
    Spina E, Avenoso A, Pollicino AM, et al. Carbamazepine coadministration with fluoxetine or fluvoxamine. Ther Drug Monit 1993; 15: 247–50PubMedCrossRefGoogle Scholar
  102. 102.
    Pearson HJ. Interaction of fluoxetine with carbamazepine. J Clin Psychiatry 1990; 51: 126PubMedGoogle Scholar
  103. 103.
    Grimsley SR, Jann MW, Carter JG, et al. Increased carbamazepine plasma concentrations after fluoxetine coadministration. Clin Pharmacol Ther 1991; 50: 10–5PubMedCrossRefGoogle Scholar
  104. 104.
    Gidal BE, Anderson GD, Seaton TL, et al. Evaluation of the effect of fluoxetine on the formation of carbamazepine epoxide. Ther Drug Monit 1993; 15: 405–9PubMedCrossRefGoogle Scholar
  105. 105.
    Swims MP. Potential terfenadine-fluoxetine interaction. Ann Pharmacother 1993; 27: 1404–5PubMedGoogle Scholar
  106. 106.
    Fritze J, Unsorg B, Lanczik M. Interaction between carbamazepine and fluvoxamine. Acta Psychiatr Scand 1991; 84:583–4PubMedCrossRefGoogle Scholar
  107. 107.
    Bonnet P, Vandel S, Nezelof S, et al. Carbamazepine, fluvoxamine: is there a pharmacokinetic interaction? Therapie 1992; 47: 165PubMedGoogle Scholar
  108. 108.
    Rapeport WG, Williams SA, Muirhead DC, et al. Absence of a sertraline-mediated effect on the pharmacokinetics and pharmacodynamics of carbamazepine. J Clin Psychiatry 1996; 57 Suppl. 1:20–3PubMedGoogle Scholar
  109. 109.
    Olkkola KT, Aranko K, Luurila H, et al. A potentially hazardous interaction between erythromycin and midazolam. Clin Pharmacol Ther 1993; 53: 298–305PubMedCrossRefGoogle Scholar
  110. 110.
    Varhe A, Olkkola KT, Neuvonen PJ. Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole and itraconazole. Clin Pharmacol Ther 1994; 56: 601–7PubMedCrossRefGoogle Scholar
  111. 111.
    Gram LF, Hansen MGJ, Sindrup SH, et al. Citalopram: interaction studies with levomepromazine, imipramine, and lithium. Ther Drug Monit 1993; 15: 18–24PubMedCrossRefGoogle Scholar
  112. 112.
    Spina E, Pollicino AM, Avenoso A, et al. Effect of fluvoxamine on the pharmacokinetics of imipramine and desipramine in healthy subjects. Ther Drug Monit 1993; 15: 243–6PubMedCrossRefGoogle Scholar
  113. 113.
    Albers LJ, Reist C, Helmeste D, et al. Paroxetine shifts imipramine metabolism. Psychiatry Res 1996; 59: 189–96PubMedCrossRefGoogle Scholar
  114. 114.
    Brøsen K, Hansen JG, Nielsen KK, et al. Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur J Clin Pharmacol 1993; 44: 349–55PubMedCrossRefGoogle Scholar
  115. 115.
    Jann MW, Carson SW, Grimsley SR, et al. Lack of effect of sertraline on the pharmacokinetics and pharmacodynamics of imipramine and its metabolites [abstract]. Clin Pharmacol Ther 1995; 57: 207Google Scholar
  116. 116.
    Sproule BA, Otton SV, Cheung SW, et al. Does sertraline inhibit CYP 2D6 after chronic dosing? Clin Pharmacol Ther 1995; 57: 151Google Scholar
  117. 117.
    Zussman BD, Davie CC, Fowles SE, et al. Sertraline, like other SSRIs, is a significant inhibitor of desipramine metabolism in vivo [abstract]. Br J Pharmacol 1995; 39: 550–1Google Scholar
  118. 118.
    Kurtz D, Bergstrom R, Goldberg M, et al. Drug interaction between sertraline and desipramine or imipramine [abstract]. J Clin Pharmacol 1994; 34: 1009–33Google Scholar
  119. 119.
    Benfield P, Ward A. Fluvoxamine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs 1986; 32: 313–34PubMedCrossRefGoogle Scholar
  120. 120.
    Apseloff G, Wilner KD, Gerber N, et al. Effect of sertraline on protein binding of warfarin. Clin Pharmacokinet 1997; 32 Suppl. 1:37–42PubMedCrossRefGoogle Scholar
  121. 121.
    Rowe H, Carmichael R, Lemberger L. The effect of fluoxetine on warfarin metabolism in the rat and man. Life Sci 1978; 23: 807–12PubMedCrossRefGoogle Scholar
  122. 122.
    Rettie AE, Korzekwa KR, Kunze KL, et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interctions. Chem Res Toxicol 1992; 5: 54–9PubMedCrossRefGoogle Scholar
  123. 123.
    Sperber AD. Toxic interaction between fluvoxamine and sustained release theophylline in an 11-year-old boy. Drug Saf 1991; 6: 460–2PubMedCrossRefGoogle Scholar
  124. 124.
    Bertschy G, Vandel S, Allers G, et al. Fluvoxamine-tricyclic antidepressant interaction. Eur J Clin Pharmacol 1991; 40: 119–20PubMedCrossRefGoogle Scholar
  125. 125.
    Ohmori S, Takeda S, Rikihisa T, et al. Studies on cytochrome P450 responsible for oxidative metabolism of imipramine in human liver microsomes. Biol Pharm Bull 1993; 16: 571–5PubMedCrossRefGoogle Scholar
  126. 126.
    Lemoine A, Gautier JC, Azoulay D, et al. Major pathway of imipramine metabolism is catalyzed by cytochromes P450 1A2 and P450 3A4 in human liver. Mol Pharmacol 1993; 43: 827–32PubMedGoogle Scholar
  127. 127.
    Schmider J, Greenblatt DJ, von Moltke LL, et al. N-demethylation of amitriptyline in vitro: role of CYP3A isoforms. Clin Pharmacol Ther 1995; 57: 193Google Scholar
  128. 128.
    Tremaine LM, Wilner KD, Preskorn SH. A study of the potential effect of sertraline on the pharmacokinetics and protein binding of tolbutamide. Clin Pharmacokinet 1997; 32 Suppl. 1: 31–6PubMedCrossRefGoogle Scholar
  129. 129.
    Veronese ME, Mackenzie PI, Doecke CJ, et al. Tolbutamide and phenytoin hydroxylations by cDNA-expressed human liver cytochrome P4502C 9. Biochem Biophys Res Commun 1991; 175: 1112–8PubMedCrossRefGoogle Scholar
  130. 130.
    Veronese ME, Doecke C, Mackenzie P, et al. Site-directed mutation studies of human liver cytochrome P-450 isoenzymes in the CYP2C subfamily. Biochem J 1993; 289 (Pt 2): 533–8PubMedGoogle Scholar
  131. 131.
    Rapeport WG, Muirhead DC, Williams SA, et al. Absence of effect of sertraline on the pharmacokinetics and pharmacodynamics of phenytoin. J Clin Psychiatry 1996; 57 Suppl. 1: 24–8PubMedGoogle Scholar
  132. 132.
    Shader RI, Greenblatt DJ, von Moltke L. Fluoxetine inhibition of phenytoin metabolism. J Clin Psychopharmacol 1994; 14: 375–6PubMedGoogle Scholar
  133. 133.
    Tassaneeyakul W, Veronese M, Birkett D, et,al. Co-regulation of phenytoin and tolbutamide metabolism in humans. Br J Clin Pharmacol 1992; 34: 494–8PubMedGoogle Scholar
  134. 134.
    Bertilsson L, Henthorn TK, Sanz E, et al. Importance of genetic factors in the regulation of diazepam metabolism: relationship to S-mephenytoin, but not debrisoquin, hydroxylation phenotype. Clin Pharmacol Ther 1989; 45: 348–55PubMedCrossRefGoogle Scholar
  135. 135.
    Andersson T. Omeprazole drug interaction studies. Clin Pharmacokinet 1991; 21: 195–212PubMedCrossRefGoogle Scholar
  136. 136.
    Ishizaki T, Chiba K, Manabe K, et al. Comparison of the effects of E3810 and omeprazole on diazepam pharmacokinetics in extensive and poor metabolizers of S-mephenytoin [abstract]. Clin Pharmacol Ther 1994; 55: 141Google Scholar
  137. 137.
    Wilkinson G, Guengerich FP, Branch RA. Genetic polymorphism of S-mephenytoin hydroxylation. Pharmacol Ther 1989; 43: 53–76PubMedCrossRefGoogle Scholar
  138. 138.
    Caraco Y, Tateishi T, Wood AJJ. Ethnic effects on inhibition of drug metabolism [abstract]. Clin Pharmacol Ther 1994; 55: 169Google Scholar
  139. 139.
    Yasumori T, Nagata K, Yang SK, et al. Cytochrome P450-mediated metabolism of diazepam in human and rat: involvement of human CYP2C in N-demethylation in the substrate concentration-dependent manner. Pharmacogenetics 1993; 3: 291–301PubMedCrossRefGoogle Scholar
  140. 140.
    Andersson T, Miners JO, Vernoese ME, et al. Diazepam metabolism by human liver microsomes is mediated by both Smephenytoin hydroxylase and CYP 3A isoforms. Br J Clin Pharmacol 1994; 38: 131–7PubMedCrossRefGoogle Scholar
  141. 141.
    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: 471–6PubMedCrossRefGoogle Scholar
  142. 142.
    Lemberger L, Rowe H, Bosomworth JC, et al. The effect of fluoxetine on the pharmacokinetics and psychomotor responses of diazepam. Clin Pharmacol Ther 1988; 43: 412–9PubMedCrossRefGoogle Scholar
  143. 143.
    Gardner MJ, Baris BA, Wilner KD, et al. Effect of sertraline on the pharmacokinetics and protein binding of diazepam in healthy volunteers. Clin Pharmacokinet 1997; 32 Suppl. 1: 43–9PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1997

Authors and Affiliations

  • Sheldon H. Preskorn
    • 1
    • 2
  1. 1.Department of PsychiatryUniversity of Kansas School of MedicineWichitaUSA
  2. 2.Psychiatric Research InstituteSt Francis Regional Medical CenterWichitaUSA

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