Skip to main content
Log in

Polymorphism of Human Cytochrome P450 2D6 and Its Clinical Significance

Part II

  • Review Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Part I of this article discussed the potential functional importance of genetic mutations and alleles of the human cytochrome P450 2D6 (CYP2D6) gene. The impact of CYP2D6 polymorphisms on the clearance of and response to a series of cardiovascular drugs was addressed. Since CYP2D6 plays a major role in the metabolism of a large number of other drugs, Part II of the article highlights the impact of CYP2D6 polymorphisms on the response to other groups of clinically used drugs.

Although clinical studies have observed a gene-dose effect for some tricyclic antidepressants, it is difficult to establish clear relationships of their pharmacokinetics and pharmacodynamic parameters to genetic variations of CYP2D6; therefore, dosage adjustment based on the CYP2D6 phenotype cannot be recommended at present. There is initial evidence for a gene-dose effect on commonly used selective serotonin reuptake inhibitors (SSRIs), but data on the effect of the CYP2D6 genotype/phenotype on the response to SSRIs and their adverse effects are scanty. Therefore, recommendations for dose adjustment of prescribed SSRIs based on the CYP2D6 genotype/phenotype may be premature.

A number of clinical studies have indicated that there are significant relationships between the CYP2D6 genotype and steady-state concentrations of perphenazine, zuclopenthixol, risperidone and haloperidol. However, findings on the relationships between the CYP2D6 genotype and parkinsonism or tardive dyskinesia treatment with traditional antipsychotics are conflicting, probably because of small sample size, inclusion of antipsychotics with variable CYP2D6 metabolism, and co-medication. CYP2D6 phenotyping and genotyping appear to be useful in predicting steady-state concentrations of some classical antipsychotic drugs, but their usefulness in predicting clinical effects must be explored. Therapeutic drug monitoring has been strongly recommended for many antipsychotics, including haloperidol, chlorpromazine, fluphenazine, perphenazine, risperidone and thioridazine, which are all metabolized by CYP2D6. It is possible to merge therapeutic drug monitoring and pharmacogenetic testing for CYP2D6 into clinical practice.

There is a clear gene-dose effect on the formation of O-demethylated metabolites from multiple opioids, but the clinical significance of this may be minimal, as the analgesic effect is not altered in poor metabolizers (PMs). Genetically caused inactivity of CYP2D6 renders codeine ineffective owing to lack of morphine formation, decreases the efficacy of tramadol owing to reduced formation of the active O-desmethyltramadol and reduces the clearance of methadone. Genetically precipitated drug interactions might render a standard opioid dose toxic.

Because of the important role of CYP2D6 in tamoxifen metabolism and activation, PMs are likely to exhibit therapeutic failure, and ultrarapid metabolizers (UMs) are likely to experience adverse effects and toxicities. There is a clear gene-concentration effect for the formation of endoxifen and 4-OH-tamoxifen. Tamoxifen-treated cancer patients carrying CYP2D6*4, *5, *10, or *41 associated with significantly decreased formation of antiestrogenic metabolites had significantly more recurrences of breast cancer and shorter relapse-free periods. Many studies have identified the genetic CYP2D6 status as an independent predictor of the outcome of tamoxifen treatment in women with breast cancer, but others have not observed this relationship. Thus, more favourable tamoxifen treatment seems to be feasible through a priori genetic assessment of CYP2D6, and proper dose adjustment may be needed when the CYP2D6 genotype is determined in a patient.

Dolasetron, ondansetron and tropisetron, all in part metabolized by CYP2D6, are less effective in UMs than in other patients. Overall, there is a strong gene-concentration relationship only for tropisetron. CYP2D6 genotype screening prior to antiemetic treatment may allow for modification of antiemetic dosing. An alternative is to use a serotonin agent that is metabolized independently of CYP2D6, such as granisetron, which would obviate the need for genotyping and may lead to an improved drug response.

To date, the functional impact of most CYP2D6 alleles has not been systematically assessed for most clinically important drugs that are mainly metabolized by CYP2D6, though some initial evidence has been identified for a very limited number of drugs. The majority of reported in vivo pharmacogenetic data on CYP2D6 are from single-dose and steady-state pharmacokinetic studies of a small number of drugs. Pharmacodynamic data on CYP2D6 polymorphisms are scanty for most drug studies. Given that genotype testing for CYP2D6 is not routinely performed in clinical practice and there is uncertainty regarding genotype-phenotype, gene-concentration and gene-dose relationships, further prospective studies on the clinical impact of CYP2D6-dependent metabolism of drugs are warranted in large cohorts.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Zhou S-F. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet 2009; 48: 689–723

    Article  PubMed  CAS  Google Scholar 

  2. Bertilsson L. Metabolism of antidepressant and neuroleptic drugs by cytochrome P450s: clinical and interethnic aspects. Clin Pharmacol Ther 2007; 82: 606–9

    Article  PubMed  CAS  Google Scholar 

  3. Hollister LE. Tricyclic antidepressants (first of two parts). N Engl J Med 1978; 299: 1106–9

    Article  PubMed  CAS  Google Scholar 

  4. Mellstrom B, von Bahr C. Demethylation and hydroxylation of amitriptyline, nortriptyline, and 10-hydroxyamitriptyline in human liver microsomes. Drug Metab Dispos 1981; 9: 565–8

    PubMed  CAS  Google Scholar 

  5. Venkatakrishnan K, Von Moltke LL, Obach RS, et al. Microsomal binding of amitriptyline: effect on estimation of enzyme kinetic parameters in vitro. J Pharmacol Exp Ther 2000; 293: 343–50

    PubMed  CAS  Google Scholar 

  6. Venkatakrishnan K, Schmider J, Harmatz JS, et al. Relative contribution of CYP3A to amitriptyline clearance in humans: in vitro and in vivo studies. J Clin Pharmacol 2001; 41: 1043–54

    Article  PubMed  CAS  Google Scholar 

  7. Olesen OV, Linnet K. Hydroxylation and demethylation of the tricyclic antidepressant nortriptyline by cDNA-expressed human cytochrome P-450 isozymes. Drug Metab Dispos 1997; 25: 740–4

    PubMed  CAS  Google Scholar 

  8. Breyer-Pfaff U. The metabolic fate of amitriptyline, nortriptyline and amitriptylinoxide in man. Drug Metab Rev 2004; 36: 723–46

    Article  PubMed  CAS  Google Scholar 

  9. Breyer-Pfaff U, Pfandl B, Nill K, et al. Enantioselective amitriptyline metabolism in patients phenotyped for two cytochrome P450 isozymes. Clin Pharmacol Ther 1992; 52: 350–8

    Article  PubMed  CAS  Google Scholar 

  10. Dahl ML, Nordin C, Bertilsson L. Enantioselective hydroxylation of nortriptyline in human liver microsomes, intestinal homogenate, and patients treated with nortriptyline. Ther Drug Monit 1991; 13: 189–94

    Article  PubMed  CAS  Google Scholar 

  11. Nordin C, Bertilsson L. Active hydroxymetabolites of antidepressants: emphasis on E-10-hydroxy-nortriptyline. Clin Pharmacokinet 1995; 28: 26–40

    Article  PubMed  CAS  Google Scholar 

  12. Mellstrom B, Sawe J, Bertilsson L, et al. Amitriptyline metabolism: association with debrisoquin hydroxylation in nonsmokers. Clin Pharmacol Ther 1986; 39: 369–71

    Article  PubMed  CAS  Google Scholar 

  13. Dahl ML, Bertilsson L, Nordin C. Steady-state plasma levels of nortriptyline and its 10-hydroxy metabolite: relationship to the CYP2D6 genotype. Psychopharmacology (Berl) 1996; 123: 315–9

    Article  CAS  Google Scholar 

  14. Mellstrom B, Bertilsson L, Sawe J, et al. E- and Z-10-hydroxylation of nortriptyline: relationship to polymorphic debrisoquine hydroxylation. Clin Pharmacol Ther 1981; 30: 189–93

    Article  PubMed  CAS  Google Scholar 

  15. Gram LF, Brosen K, Kragh-Sorensen 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: 508–14

    Article  PubMed  CAS  Google Scholar 

  16. Dalen P, Dahl ML, Bernal Ruiz ML, et al. 10-Hydroxylation of nortriptyline in White persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes. Clin Pharmacol Ther 1998; 63: 444–52

    Article  PubMed  CAS  Google Scholar 

  17. Yue QY, Zhong ZH, Tybring G, et al. Pharmacokinetics of nortriptyline and its 10-hydroxy metabolite in Chinese subjects of different CYP2D6 genotypes. Clin Pharmacol Ther 1998; 64: 384–90

    Article  PubMed  CAS  Google Scholar 

  18. Morita S, Shimoda K, Someya T, et al. Steady-state plasma levels of nortriptyline and its hydroxylated metabolites in Japanese patients: impact of CYP2D6 genotype on the hydroxylation of nortriptyline. J Clin Psychopharmacol 2000; 20: 141–9

    Article  PubMed  CAS  Google Scholar 

  19. Halling J, Weihe P, Brosen K. The CYP2D6 polymorphism in relation to the metabolism of amitriptyline and nortriptyline in the Faroese population. Br J Clin Pharmacol 2008; 65: 134–8

    Article  PubMed  CAS  Google Scholar 

  20. Steimer W, Zopf K, von Amelunxen S, et al. Amitriptyline or not, that is the question: pharmacogenetic testing of CYP2D6 and CYP2C19 identifies patients with low or high risk for side effects in amitriptyline therapy. Clin Chem 2005; 51: 376–85

    Article  PubMed  CAS  Google Scholar 

  21. Roberts RL, Mulder RT, Joyce PR, et al. No evidence of increased adverse drug reactions in cytochrome P450 CYP2D6 poor metabolizers treated with fluoxetine or nortriptyline. Hum Psychopharmacol 2004; 19: 17–23

    Article  PubMed  CAS  Google Scholar 

  22. van der Kuy PH, Hooymans PM. Nortriptyline intoxication induced by terbinafine. BMJ 1998; 316: 441

    Article  PubMed  Google Scholar 

  23. Bertilsson L, Aberg-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: 478–80

    Article  PubMed  CAS  Google Scholar 

  24. Peters II MD, Davis SK, Austin LS. Clomipramine: an antiobsessional tricyclic antidepressant. Clin Pharm 1990; 9: 165–78

    PubMed  CAS  Google Scholar 

  25. Balant-Gorgia AE, Gex-Fabry M, Balant LP. Clinical pharmacokinetics of clomipramine. Clin Pharmacokinet 1991; 20: 447–62

    Article  PubMed  CAS  Google Scholar 

  26. Nielsen KK, Flinois JP, Beaune P, et al. The biotransformation of clomipramine in vitro, identification of the cytochrome P450s responsible for the separate metabolic pathways. J Pharmacol Exp Ther 1996; 277: 1659–64

    PubMed  CAS  Google Scholar 

  27. Nielsen KK, Brosen K, Hansen MG, et al. Single-dose kinetics of clomipramine: relationship to the sparteine and S-mephenytoin oxidation polymorphisms. Clin Pharmacol Ther 1994; 55: 518–27

    Article  PubMed  CAS  Google Scholar 

  28. Nielsen KK, Brosen K, Gram LF. Steady-state plasma levels of clomipramine and its metabolites: impact of the sparteine/debrisoquine oxidation polymorphism. Danish University Antidepressant Group. Eur J Clin Pharmacol 1992; 43:405–11

    Article  PubMed  CAS  Google Scholar 

  29. Sindrup SH, Gram LF, Skjold T, et al. Clomipramine vs desipramine vs placebo in the treatment of diabetic neuropathy symptoms: a double-blind cross-over study. Br J Clin Pharmacol 1990; 30: 683–91

    Article  PubMed  CAS  Google Scholar 

  30. Pinder RM, Brogden RN, Speight TM, et al. Doxepin up-to-date: a review of its pharmacological properties and therapeutic efficacy with particular reference to depression. Drugs 1977; 13: 161–218

    Article  PubMed  CAS  Google Scholar 

  31. Shu YZ, Hubbard JW, Cooper JK, et al. The identification of urinary metabolites of doxepin in patients. Drug Metab Dispos 1990; 18: 735–41

    PubMed  CAS  Google Scholar 

  32. Haritos VS, Ghabrial H, Ahokas JT, et al. Role of cytochrome P450 2D6 (CYP2D6) in the stereospecific metabolism of E- and Z-doxepin. Pharmacogenetics 2000; 10: 591–603

    Article  PubMed  CAS  Google Scholar 

  33. Hartter S, Tybring G, Friedberg T, et al. The N-demethylation of the doxepin isomers is mainly catalyzed by the polymorphic CYP2C19. Pharm Res 2002; 19: 1034–7

    Article  PubMed  Google Scholar 

  34. Kirchheiner J, Meineke I, Muller G, et al. Contributions of CYP2D6, CYP2C9 and CYP2C19 to the biotransformation of E- and Z-doxepin in healthy volunteers. Pharmacogenetics 2002; 12: 571–80

    Article  PubMed  CAS  Google Scholar 

  35. Koski A, Ojanpera I, Sistonen J, et al. A fatal doxepin poisoning associated with a defective CYP2D6 genotype. Am J Forensic Med Pathol 2007; 28: 259–61

    Article  PubMed  Google Scholar 

  36. Sallee FR, Pollock BG. Clinical pharmacokinetics of imipramine and desipramine. Clin Pharmacokinet 1990; 18: 346–64

    Article  PubMed  CAS  Google Scholar 

  37. Lemoine A, Gautier JC, Azoulay D, et al. Major pathway of imipramine metabolism is catalyzed by cytochromes P-450 1A2 and P-450 3A4 in human liver. Mol Pharmacol 1993; 43: 827–32

    PubMed  CAS  Google Scholar 

  38. Koyama E, Chiba K, Tani M, et al. Reappraisal of human CYP isoforms involved in imipramine N-demethylation and 2-hydroxylation: a study using microsomes obtained from putative extensive and poor metabolizers of S-mephenytoin and eleven recombinant human CYPs. J Pharmacol Exp Ther 1997; 281: 1199–210

    PubMed  CAS  Google Scholar 

  39. Brosen K, Zeugin T, Meyer UA. Role of P450IID6, the target of the sparteinedebrisoquin oxidation polymorphism, in the metabolism of imipramine. Clin Pharmacol Ther 1991; 49: 609–17

    Article  PubMed  CAS  Google Scholar 

  40. Nakajima M, Tanaka E, Kobayashi T, et al. Imipramine N-glucuronidation in human liver microsomes: biphasic kinetics and characterization of UDP-glucuronosyltransferase isoforms. Drug Metab Dispos 2002; 30: 636–42

    Article  PubMed  CAS  Google Scholar 

  41. Koyama E, Kikuchi Y, Echizen H, et al. Simultaneous high-performance liquid chromatography-electrochemical detection determination of imipramine, desipramine, their 2-hydroxylated metabolites, and imipramine N-oxide in human plasma and urine: preliminary application to oxidation pharmacogenetics. Ther Drug Monit 1993; 15: 224–35

    Article  PubMed  CAS  Google Scholar 

  42. Brosen K, Otton SV, Gram LF. Imipramine demethylation and hydroxylation: impact of the sparteine oxidation phenotype. Clin Pharmacol Ther 1986; 40: 543–9

    Article  PubMed  CAS  Google Scholar 

  43. Spina E, Steiner E, Ericsson O, et al. Hydroxylation of desmethylimipramine: dependence on the debrisoquin hydroxylation phenotype. Clin Pharmacol Ther 1987; 41: 314–9

    Article  PubMed  CAS  Google Scholar 

  44. Steiner E, Spina E. Differences in the inhibitory effect of cimetidine on desipramine metabolism between rapid and slow debrisoquin hydroxylators. Clin Pharmacol Ther 1987; 42: 278–82

    Article  PubMed  CAS  Google Scholar 

  45. Spina E, Gitto C, Avenoso A, et al. Relationship between plasma desipramine levels, CYP2D6 phenotype and clinical response to desipramine: a prospective study. Eur J Clin Pharmacol 1997; 51: 395–8

    Article  PubMed  CAS  Google Scholar 

  46. Shimoda K, Morita S, Hirokane G, et al. Metabolism of desipramine in Japanese psychiatric patients: the impact of CYP2D6 genotype on the hydroxylation of desipramine. Pharmacol Toxicol 2000; 86: 245–9

    Article  PubMed  CAS  Google Scholar 

  47. Brosen K, Klysner R, Gram LF, et al. Steady-state concentrations of imipramine and its metabolites in relation to the sparteine/debrisoquine polymorphism. Eur J Clin Pharmacol 1986; 30: 679–84

    Article  PubMed  CAS  Google Scholar 

  48. Sindrup SH, Brosen K, Gram LF. Nonlinear kinetics of imipramine in low and medium plasma level ranges. Ther Drug Monit 1990; 12: 445–9

    Article  PubMed  CAS  Google Scholar 

  49. Schenk PW, van Fessem MA, Verploegh-Van Rij S, et al. Association of graded allele-specific changes in CYP2D6 function with imipramine dose requirement in a large group of depressed patients. Mol Psychiatry 2008; 13: 597–605

    Article  PubMed  CAS  Google Scholar 

  50. Pinder RM, Brogden RN, Speight TM, et al. Maprotiline: a review of its pharmacological properties and therapeutic efficacy in mental depressive states. Drugs 1977; 13: 321–52

    Article  PubMed  CAS  Google Scholar 

  51. Brachtendorf L, Jetter A, Beckurts KT, et al. Cytochrome P450 enzymes contributing to demethylation of maprotiline in man. Pharmacol Toxicol 2002; 90: 144–9

    Article  PubMed  CAS  Google Scholar 

  52. Breyer-Pfaff U, Kroeker M, Winkler T, et al. Isolation and identification of hydroxylated maprotiline metabolites. Xenobiotica 1985; 15: 57–66

    Article  PubMed  CAS  Google Scholar 

  53. Hartter S, Wetzel H, Hammes E, et al. Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine in depressed patients. Psychopharmacology (Berl) 1993; 110: 302–8

    Article  CAS  Google Scholar 

  54. Normann C, Lieb K, Walden J. Increased plasma concentration of maprotiline by coadministration of risperidone. J Clin Psychopharmacol 2002; 22: 92–4

    Article  PubMed  Google Scholar 

  55. Konig F, Wolfersdorf M, Loble M, et al. Trimipramine and maprotiline plasma levels during combined treatment with moclobemide in therapy-resistant depression. Pharmacopsychiatry 1997; 30: 125–7

    Article  PubMed  CAS  Google Scholar 

  56. 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: 670–7

    Article  PubMed  CAS  Google Scholar 

  57. Firkusny L, Gleiter CH. Maprotiline metabolism appears to co-segregate with the genetically-determined CYP2D6 polymorphic hydroxylation of debrisoquine. Br J Clin Pharmacol 1994; 37: 383–8

    Article  PubMed  CAS  Google Scholar 

  58. Gastpar M. Clinical originality and new biology of trimipramine. Drugs 1989; 38 Suppl. 1: 43–8; discussion 49-50

    Article  PubMed  Google Scholar 

  59. Bolaji OO, Coutts RT, Baker GB. Metabolism of trimipramine in vitro by human CYP2D6 isozyme. Res Commun Chem Pathol Pharmacol 1993; 82: 111–20

    PubMed  CAS  Google Scholar 

  60. Eap CB, Bender S, Gastpar M, et al. Steady state plasma levels of the enantiomers of trimipramine and of its metabolites in CYP2D6-, CYP2C19-and CYP3A4/5-phenotyped patients. Ther Drug Monit 2000; 22: 209–14

    Article  PubMed  CAS  Google Scholar 

  61. Kirchheiner J, Muller G, Meineke I, et al. Effects of polymorphisms in CYP2D6, CYP2C9, and CYP2C19 on trimipramine pharmacokinetics. J Clin Psychopharmacol 2003; 23: 459–66

    Article  PubMed  CAS  Google Scholar 

  62. Eap CB, Laurian S, Souche A, et al. Influence of quinidine on the pharmacokinetics of trimipramine and on its effect on the waking EEG of healthy volunteers: a pilot study on two subjects. Neuropsychobiology 1992; 25: 214–20

    Article  PubMed  CAS  Google Scholar 

  63. Leinonen E, Koponen HJ, Lepola U. Paroxetine increases serum trimipramine concentration: a report of two cases. Human Psychopharmacol Clin Exp 2004; 10: 345–7

    Article  Google Scholar 

  64. Musshoff F, Schmidt P, Madea B. Fatality caused by a combined trimipramine-citalopram intoxication. Forensic Sci Int 1999; 106: 125–31

    Article  PubMed  CAS  Google Scholar 

  65. Caccia S. Metabolism of the newer antidepressants: an overview of the pharmacological and pharmacokinetic implications. Clin Pharmacokinet 1998; 34: 281–302

    Article  PubMed  CAS  Google Scholar 

  66. Hiemke C, Hartter S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther 2000; 85: 11–28

    Article  PubMed  CAS  Google Scholar 

  67. Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors: an overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet 1997; 32 Suppl. 1: 1–21

    Article  PubMed  CAS  Google Scholar 

  68. Fogelman SM, Schmider J, Venkatakrishnan K, et al. O- and N-demethylation of venlafaxine in vitro by human liver microsomes and by microsomes from cDNA-transfected cells: effect of metabolic inhibitors and SSRI antidepressants. Neuropsychopharmacology 1999; 20: 480–90

    Article  PubMed  CAS  Google Scholar 

  69. Rao N. The clinical pharmacokinetics of escitalopram. Clin Pharmacokinet 2007; 46: 281–90

    Article  PubMed  CAS  Google Scholar 

  70. Olesen OV, Linnet K. Studies on the stereoselective metabolism of citalopram by human liver microsomes and cDNA-expressed cytochrome P450 enzymes. Pharmacology 1999; 59: 298–309

    Article  PubMed  CAS  Google Scholar 

  71. von Moltke LL, Greenblatt DJ, Giancarlo GM, et al. Escitalopram (S-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to R-citalopram. Drug Metab Dispos 2001; 29: 1102–9

    Google Scholar 

  72. Herrlin K, Yasui-Furukori N, Tybring G, et al. Metabolism of citalopram enantiomers in CYP2C19/CYP2D6 phenotyped panels of healthy Swedes. Br J Clin Pharmacol 2003; 56: 415–21

    Article  PubMed  CAS  Google Scholar 

  73. Peters EJ, Slager SL, Kraft JB, et al. Pharmacokinetic genes do not influence response or tolerance to citalopram in the STAR*D sample. PLoS ONE 2008; 3: e1872

    Article  PubMed  CAS  Google Scholar 

  74. Reis M, Lundmark J, Bengtsson F. Therapeutic drug monitoring of racemic citalopram: a 5-year experience in Sweden, 1992–1997. Ther Drug Monit 2003; 25: 183–91

    Article  PubMed  CAS  Google Scholar 

  75. Figgitt DP, McClellan KJ. Fluvoxamine: an updated review of its use in the management of adults with anxiety disorders. Drugs 2000; 60: 925–54

    Article  PubMed  CAS  Google Scholar 

  76. Wilde MI, Plosker GL, Benfield P. Fluvoxamine: an updated review of its pharmacology, and therapeutic use in depressive illness. Drugs 1993; 46: 895–924

    Article  PubMed  CAS  Google Scholar 

  77. Spigset O, Granberg K, Hagg S, et al. Non-linear fluvoxamine disposition. Br J Clin Pharmacol 1998; 45: 257–63

    Article  PubMed  CAS  Google Scholar 

  78. Perucca E, Gatti G, Spina E. Clinical pharmacokinetics of fluvoxamine. Clin Pharmacokinet 1994; 27: 175–90

    Article  PubMed  CAS  Google Scholar 

  79. Spigset O, Axelsson S, Norstrom A, et al. The major fluvoxamine metabolite in urine is formed by CYP2D6. Eur J Clin Pharmacol 2001; 57: 653–8

    Article  PubMed  CAS  Google Scholar 

  80. DeVane CL, Gill HS. Clinical pharmacokinetics of fluvoxamine: applications to dosage regimen design. J Clin Psychiatry 1997; 58 Suppl. 5: 7–14

    PubMed  CAS  Google Scholar 

  81. van Harten J. Overview of the pharmacokinetics of fluvoxamine. Clin Pharmacokinet 1995; 29 Suppl. 1: 1–9

    Article  PubMed  Google Scholar 

  82. Spina E, Santoro V, D’Arrigo C. Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update. Clin Ther 2008; 30: 1206–27

    Article  PubMed  CAS  Google Scholar 

  83. Wagner W, Vause EW. Fluvoxamine: a review of global drug-drug interaction data. Clin Pharmacokinet 1995; 29 Suppl. 1: 26–31; discussion 31-2

    Article  PubMed  CAS  Google Scholar 

  84. Christensen M, Tybring G, Mihara K, et al. Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). Clin Pharmacol Ther 2002; 71: 141–52

    Article  PubMed  CAS  Google Scholar 

  85. Suzuki Y, Sawamura K, Someya T. Polymorphisms in the 5-hydroxytryptamine 2A receptor and cytochrome P4502D6 genes synergistically predict fluvoxamine-induced side effects in Japanese depressed patients. Neuropsychopharmacology 2006; 31: 825–31

    Article  PubMed  CAS  Google Scholar 

  86. Kirchheiner J, Brosen K, Dahl ML, et al. CYP2D6 and CYP2C19 genotypebased dose recommendations for antidepressants: a first step towards subpopulation-specific dosages. Acta Psychiatr Scand 2001; 104: 173–92

    Article  PubMed  CAS  Google Scholar 

  87. Mandrioli R, Forti GC, Raggi MA. Fluoxetine metabolism and pharmacological interactions: the role of cytochrome P450. Curr Drug Metab 2006; 7: 127–33

    Article  PubMed  CAS  Google Scholar 

  88. Margolis JM, O’Donnell JP, Mankowski DC, et al. (R)-, (S)-, and racemic fluoxetine N-demethylation by human cytochrome P450 enzymes. Drug Metab Dispos 2000; 28: 1187–91

    PubMed  CAS  Google Scholar 

  89. Ring BJ, Eckstein JA, Gillespie JS, et al. Identification of the human cytochromes P450 responsible for in vitro formation of R- and S-norfluoxetine. J Pharmacol Exp Ther 2001; 297: 1044–50

    PubMed  CAS  Google Scholar 

  90. Hamelin BA, Turgeon J, Vallee F, et al. The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin. Clin Pharmacol Ther 1996; 60: 512–21

    Article  PubMed  CAS  Google Scholar 

  91. Fjordside L, Jeppesen U, Eap CB, et al. The stereoselective metabolism of fluoxetine in poor and extensive metabolizers of sparteine. Pharmacogenetics 1999; 9: 55–60

    Article  PubMed  CAS  Google Scholar 

  92. Scordo MG, Spina E, Dahl ML, et al. Influence of CYP2C9, 2C19 and 2D6 genetic polymorphisms on the steady-state plasma concentrations of the enantiomers of fluoxetine and norfluoxetine. Basic Clin Pharmacol Toxicol 2005; 97: 296–301

    Article  PubMed  CAS  Google Scholar 

  93. Stedman CA, Begg EJ, Kennedy MA, et al. Cytochrome P450 2D6 genotype does not predict SSRI (fluoxetine or paroxetine) induced hyponatraemia. Hum Psychopharmacol 2002; 17: 187–90

    Article  PubMed  CAS  Google Scholar 

  94. Gunasekara NS, Noble S, Benfield P. Paroxetine: an update of its pharmacology and therapeutic use in depression and a review of its use in other disorders. Drugs 1998; 55: 85–120

    Article  PubMed  CAS  Google Scholar 

  95. 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: 521–3

    Article  PubMed  CAS  Google Scholar 

  96. Sindrup SH, Brosen K, Gram LF, et al. The relationship between paroxetine and the sparteine oxidation polymorphism. Clin Pharmacol Ther 1992; 51: 278–87

    Article  PubMed  CAS  Google Scholar 

  97. Sindrup SH, Brosen K, Gram LF. Pharmacokinetics of the selective serotonin reuptake inhibitor paroxetine: nonlinearity and relation to the sparteine oxidation polymorphism. Clin Pharmacol Ther 1992; 51: 288–95

    Article  PubMed  CAS  Google Scholar 

  98. Ozdemir V, Tyndale RF, Reed K, et al. Paroxetine steady-state plasma concentration in relation to CYP2D6 genotype in extensive metabolizers. J Clin Psychopharmacol 1999; 19: 472–5

    Article  PubMed  CAS  Google Scholar 

  99. Lam YW, Gaedigk A, Ereshefsky L, et al. CYP2D6 inhibition by selective serotonin reuptake inhibitors: analysis of achievable steady-state plasma concentrations and the effect of ultrarapid metabolism at CYP2D6. Pharmacotherapy 2002; 22: 1001–6

    Article  PubMed  CAS  Google Scholar 

  100. Charlier C, Broly F, Lhermitte M, et al. Polymorphisms in the CYP2D6 gene: association with plasma concentrations of fluoxetine and paroxetine. Ther Drug Monit 2003; 25: 738–42

    Article  PubMed  CAS  Google Scholar 

  101. Zourkova A, Hadasova E. Relationship between CYP 2D6 metabolic status and sexual dysfunction in paroxetine treatment. J Sex Marital Ther 2002; 28: 451–61

    Article  PubMed  Google Scholar 

  102. Murphy Jr GM, Kremer C, Rodrigues S, et al. Pharmacogenetics of antidepressant medication intolerance. Am J Psychiatry 2003; 160: 1830–5

    Article  PubMed  Google Scholar 

  103. Tanaka M, Kobayashi D, Murakami Y, et al. Genetic polymorphisms in the 5-hydroxytryptamine type 3B receptor gene and paroxetine-induced nausea. Int J Neuropsychopharmacol 2008; 11: 261–7

    Article  PubMed  CAS  Google Scholar 

  104. Pinder RM, Van Delft AM. The potential therapeutic role of the enantiomers and metabolites of mianserin. Br J Clin Pharmacol 1983; 15 Suppl. 2: 269–76S

    Article  CAS  Google Scholar 

  105. Delbressine LP, Moonen ME, Kaspersen FM, et al. Biotransformation of mianserin in laboratory animals and man. Xenobiotica 1992; 22: 227–36

    Article  PubMed  CAS  Google Scholar 

  106. Stormer E, von Moltke LL, Shader RI, et al. Metabolism of the antidepressant mirtazapine in vitro: contribution of cytochromes P-450 1A2, 2D6, and 3A4. Drug Metab Dispos 2000; 28: 1168–75

    PubMed  CAS  Google Scholar 

  107. Koyama E, Chiba K, Tani M, et al. Identification of human cytochrome P450 isoforms involved in the stereoselective metabolism of mianserin enantiomers. J Pharmacol Exp Ther 1996; 278: 21–30

    PubMed  CAS  Google Scholar 

  108. Dahl ML, Tybring G, Elwin CE, et al. Stereoselective disposition of mianserin is related to debrisoquin hydroxylation polymorphism. Clin Pharmacol Ther 1994; 56: 176–83

    Article  PubMed  CAS  Google Scholar 

  109. Yasui N, Tybring G, Otani K, et al. Effects of thioridazine, an inhibitor of CYP2D6, on the steady-state plasma concentrations of the enantiomers of mianserin and its active metabolite, desmethylmianserin, in depressed Japanese patients. Pharmacogenetics 1997; 7: 369–74

    Article  PubMed  CAS  Google Scholar 

  110. Sindrup SH, Tuxen C, Gram LF, et al. Lack of effect of mianserin on the symptoms of diabetic neuropathy. Eur J Clin Pharmacol 1992; 43: 251–5

    Article  PubMed  CAS  Google Scholar 

  111. Tacke U, Leinonen E, Lillsunde P, et al. Debrisoquine hydroxylation phenotypes of patients with high versus low to normal serum antidepressant concentrations. J Clin Psychopharmacol 1992; 12: 262–7

    Article  PubMed  CAS  Google Scholar 

  112. Begg EJ, Sharman JR, Kidd JE, et al. Variability in the elimination of mianserin in elderly patients. Br J Clin Pharmacol 1989; 27: 445–51

    Article  PubMed  CAS  Google Scholar 

  113. Mihara K, Otani K, Tybring G, et al. The CYP2D6 genotype and plasma concentrations of mianserin enantiomers in relation to therapeutic response to mianserin in depressed Japanese patients. J Clin Psychopharmacol 1997; 17: 467–71

    Article  PubMed  CAS  Google Scholar 

  114. Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev 2001; 7: 249–64

    Article  PubMed  CAS  Google Scholar 

  115. Timmer CJ, Sitsen JM, Delbressine LP. Clinical pharmacokinetics of mirtazapine. Clin Pharmacokinet 2000; 38: 461–74

    Article  PubMed  CAS  Google Scholar 

  116. Delbressine LP, Moonen ME, Kaspersen FM, et al. Pharmacokinetics and biotransformation of mirtazapine in human volunteers. Clin Drug Investig 1998; 15: 45–55

    Article  PubMed  CAS  Google Scholar 

  117. Grasmader K, Verwohlt PL, Kuhn KU, et al. Population pharmacokinetic analysis of mirtazapine. Eur J Clin Pharmacol 2004; 60: 473–80

    Article  PubMed  CAS  Google Scholar 

  118. Kirchheiner J, Henckel HB, Meineke I, et al. Impact of the CYP2D6 ultrarapid metabolizer genotype on mirtazapine pharmacokinetics and adverse events in healthy volunteers. J Clin Psychopharmacol 2004; 24: 647–52

    Article  PubMed  CAS  Google Scholar 

  119. Brockmoller J, Meineke I, Kirchheiner J. Pharmacokinetics of mirtazapine: enantioselective effects of the CYP2D6 ultra rapid metabolizer genotype and correlation with adverse effects. Clin Pharmacol Ther 2007; 81: 699–707

    Article  PubMed  CAS  Google Scholar 

  120. Holliday SM, Benfield P. Venlafaxine: a review of its pharmacology and therapeutic potential in depression. Drugs 1995; 49: 280–94

    Article  PubMed  CAS  Google Scholar 

  121. Ellingrod VL, Perry PJ. Venlafaxine: a heterocyclic antidepressant. Am J Hosp Pharm 1994; 51: 3033–46

    PubMed  CAS  Google Scholar 

  122. Otton SV, Ball SE, Cheung SW, et al. Venlafaxine oxidation in vitro is catalysed by CYP2D6. Br J Clin Pharmacol 1996; 41: 149–56

    Article  PubMed  CAS  Google Scholar 

  123. Lindh JD, Annas A, Meurling L, et al. Effect of ketoconazole on venlafaxine plasma concentrations in extensive and poor metabolisers of debrisoquine. Eur J Clin Pharmacol 2003; 59: 401–6

    Article  PubMed  CAS  Google Scholar 

  124. Lessard E, Yessine MA, Hamelin BA, et al. Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of the antidepressant agent venlafaxine in humans. Pharmacogenetics 1999; 9: 435–43

    Article  PubMed  CAS  Google Scholar 

  125. Veefkind AH, Haffmans PM, Hoencamp E. Venlafaxine serum levels and CYP2D6 genotype. Ther Drug Monit 2000; 22: 202–8

    Article  PubMed  CAS  Google Scholar 

  126. Fukuda T, Nishida Y, Zhou Q, et al. The impact of the CYP2D6 and CYP2C19 genotypes on venlafaxine pharmacokinetics in a Japanese population. Eur J Clin Pharmacol 2000; 56: 175–80

    Article  PubMed  CAS  Google Scholar 

  127. Eap CB, Lessard E, Baumann P, et al. Role of CYP2D6 in the stereoselective disposition of venlafaxine in humans. Pharmacogenetics 2003; 13: 39–47

    Article  PubMed  CAS  Google Scholar 

  128. Whyte EM, Romkes M, Mulsant BH, et al. CYP2D6 genotype and venlafaxine-XR concentrations in depressed elderly. Int J Geriatr Psychiatry 2006; 21: 542–9

    Article  PubMed  Google Scholar 

  129. Shams ME, Arneth B, Hiemke C, et al. CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine. J Clin Pharm Ther 2006; 31:493–502

    Article  PubMed  CAS  Google Scholar 

  130. Hermann M, Hendset M, Fosaas K, et al. Serum concentrations of venlafaxine and its metabolites O-desmethylvenlafaxine and N-desmethylvenlafaxine in heterozygous carriers of the CYP2D6*3, *4 or *5 allele. Eur J Clin Pharmacol 2008; 64: 483–7

    Article  PubMed  CAS  Google Scholar 

  131. McAlpine DE, O’Kane DJ, Black JL, et al. Cytochrome P450 2D6 genotype variation and venlafaxine dosage. Mayo Clin Proc 2007; 82: 1065–8

    Article  PubMed  CAS  Google Scholar 

  132. Xu ZH, Wang W, Zhao XJ, et al. Evidence for involvement of polymorphic CYP2C19 and 2C9 in the N-demethylation of sertraline in human livermicrosomes. Br J Clin Pharmacol 1999; 48: 416–23

    Article  PubMed  CAS  Google Scholar 

  133. Bertilsson L, Mellstrom B, Sjokvist F, et al. Slow hydroxylation of nortriptyline and concomitant poor debrisoquine hydroxylation: clinical implications. Lancet 1981; 1: 560–1

    Article  PubMed  CAS  Google Scholar 

  134. Bluhm RE, Wilkinson GR, Shelton R, et al. Genetically determined drugmetabolizing activity and desipramine-associated cardiotoxicity: a case report. Clin Pharmacol Ther 1993; 53: 89–95

    Article  PubMed  CAS  Google Scholar 

  135. Bertilsson L, Dahl ML, Sjoqvist F, et al. Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet 1993; 341:63

    Article  PubMed  CAS  Google Scholar 

  136. Rau T, Wohlleben G, Wuttke H, et al. CYP2D6 genotype: impact on adverse effects and nonresponse during treatment with antidepressants. A pilot study. Clin Pharmacol Ther 2004; 75: 386–93

    Article  PubMed  CAS  Google Scholar 

  137. Kawanishi C, Lundgren S, Agren H, et al. Increased incidence of CYP2D6 gene duplication in patients with persistent mood disorders: ultrarapid metabolism of antidepressants as a cause of nonresponse. A pilot study. Eur J Clin Pharmacol 2004; 59: 803–7

    Article  PubMed  CAS  Google Scholar 

  138. Grasmader K, Verwohlt PL, Rietschel M, et al. Impact of polymorphisms of cytochrome-P450 isoenzymes 2C9, 2C19 and 2D6 on plasma concentrations and clinical effects of antidepressants in a naturalistic clinical setting. Eur J Clin Pharmacol 2004; 60: 329–36

    PubMed  Google Scholar 

  139. Bijl MJ, Visser LE, Hofman A, et al. Influence of the CYP2D6*4 polymorphism on dose, switching and discontinuation of antidepressants. Br J Clin Pharmacol 2008; 65: 558–64

    Article  PubMed  CAS  Google Scholar 

  140. Kwadijk-de Gijsel S, Bijl MJ, Visser LE, et al. Variation in the CYP2D6 gene is associated with a lower serum sodium concentration in patients on antidepressants. Br J Clin Pharmacol 2009; 68: 221–5

    Article  PubMed  CAS  Google Scholar 

  141. Seeringer A, Kirchheiner J. Pharmacogenetics-guided dose modifications of antidepressants. Clin Lab Med 2008; 28: 619–26

    Article  PubMed  Google Scholar 

  142. Lieberman JA, Bymaster FP, Meltzer HY, et al. Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection. Pharmacol Rev 2008; 60: 358–403

    Article  PubMed  CAS  Google Scholar 

  143. Worrel JA, Marken PA, Beckman SE, et al. Atypical antipsychotic agents: a critical review. Am J Health Syst Pharm 2000; 57: 238–55

    PubMed  CAS  Google Scholar 

  144. Vohora D. Atypical antipsychotic drugs: current issues of safety and efficacy in the management of schizophrenia. Curr Opin Investig Drugs 2007; 8: 531–8

    PubMed  CAS  Google Scholar 

  145. Moller HJ. Risperidone: a review. Expert Opin Pharmacother 2005; 6: 803–18

    Article  PubMed  Google Scholar 

  146. Bishara D, Taylor D. Upcoming agents for the treatment of schizophrenia: mechanism of action, efficacy and tolerability. Drugs 2008; 68: 2269–92

    Article  PubMed  CAS  Google Scholar 

  147. Gardiner SJ, Begg EJ. Pharmacogenetics drug-metabolizing enzymes, and clinical practice. Pharmacol Rev 2006; 58: 521–90

    Article  PubMed  CAS  Google Scholar 

  148. Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenom J 2005; 5: 6–13

    Article  CAS  Google Scholar 

  149. Zhou SF, Di YM, Chan E, et al. Clinical pharmacogenetics and potential application in personalized medicine. Curr Drug Metab 2008; 9: 738–84

    Article  PubMed  CAS  Google Scholar 

  150. Swainston Harrison T, Perry CM. Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder. Drugs 2004; 64: 1715–36

    Article  PubMed  Google Scholar 

  151. Shapiro DA, Renock S, Arrington E, et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology 2003; 28: 1400–11

    Article  PubMed  CAS  Google Scholar 

  152. Molden E, Lunde H, Lunder N, et al. Pharmacokinetic variability of aripiprazole and the active metabolite dehydroaripiprazole in psychiatric patients. Ther Drug Monit 2006; 28: 744–9

    Article  PubMed  CAS  Google Scholar 

  153. Kubo M, Koue T, Inaba A, et al. Influence of itraconazole co-administration and CYP2D6 genotype on the pharmacokinetics of the new antipsychotic aripiprazole. Drug Metab Pharmacokinet 2005; 20: 55–64

    Article  PubMed  CAS  Google Scholar 

  154. Kim JR, Seo HB, Cho JY, et al. Population pharmacokinetic modelling of aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patients. Br J Clin Pharmacol 2008; 66: 802–10

    Article  PubMed  CAS  Google Scholar 

  155. Koue T, Kubo M, Funaki T, et al. Nonlinear mixed effects model analysis of the pharmacokinetics of aripiprazole in healthy Japanese males. Biol Pharm Bull 2007; 30: 2154–8

    Article  PubMed  CAS  Google Scholar 

  156. Kubo M, Koue T, Maune H, et al. Pharmacokinetics of aripiprazole, a new antipsychotic, following oral dosing in healthy adult Japanese volunteers: influence of CYP2D6 polymorphism. Drug Metab Pharmacokinet 2007; 22: 358–66

    Article  PubMed  CAS  Google Scholar 

  157. Hendset M, Hermann M, Lunde H, et al. Impact of the CYP2D6 genotype on steady-state serum concentrations of aripiprazole and dehydroaripiprazole. Eur J Clin Pharmacol 2007; 63: 1147–51

    Article  PubMed  CAS  Google Scholar 

  158. Oosterhuis M, Van De Kraats G, Tenback D. Safety of aripiprazole: high serum levels in a CYP2D6 mutated patient. Am J Psychiatry 2007; 164: 175

    Article  PubMed  Google Scholar 

  159. Waade RB, Christensen H, Rudberg I, et al. Influence of comedication on serum concentrations of aripiprazole and dehydroaripiprazole. Ther Drug Monit 2009; 31: 233–8

    Article  PubMed  CAS  Google Scholar 

  160. Hartmann F, Gruenke LD, Craig JC, et al. Chlorpromazine metabolism in extracts of liver and small intestine from guinea pig and from man. Drug Metab Dispos 1983; 11: 244–8

    PubMed  CAS  Google Scholar 

  161. Yoshii K, Kobayashi K, Tsumuji M, et al. Identification of human cytochrome P450 isoforms involved in the 7-hydroxylation of chlorpromazine by human liver microsomes. Life Sci 2000; 67: 175–84

    Article  PubMed  CAS  Google Scholar 

  162. Muralidharan G, Cooper JK, Hawes EM, et al. Quinidine inhibits the 7-hydroxylation of chlorpromazine in extensive metabolisers of debrisoquine. Eur J Clin Pharmacol 1996; 50: 121–8

    Article  PubMed  CAS  Google Scholar 

  163. Sunwoo YE, Ryu J, Jung H, et al. Disposition of chlorpromazine in Korean healthy subjects with CYP2D6 wild-type and *10B mutation [abstract]. Clin Pharmacol Ther 2004; 73: PII–146

    Google Scholar 

  164. Kudo S, Ishizaki T. Pharmacokinetics of haloperidol: an update. Clin Pharmacokinet 1999; 37: 435–56

    Article  PubMed  CAS  Google Scholar 

  165. Yatham LN. The role of novel antipsychotics in bipolar disorders. J Clin Psychiatry 2002; 63: 10–4

    Article  PubMed  CAS  Google Scholar 

  166. Tateishi T, Watanabe M, Kumai T, et al. CYP3A is responsible for N-dealkylation of haloperidol and bromperidol and oxidation of their reduced forms by human liver microsomes. Life Sci 2000; 67: 2913–20

    Article  PubMed  CAS  Google Scholar 

  167. Kudo S, Odomi M. Involvement of human cytochrome P450 3A4 in reduced haloperidol oxidation. Eur J Clin Pharmacol 1998; 54: 253–9

    Article  PubMed  CAS  Google Scholar 

  168. Pan LP, De Vriendt C, Belpaire FM. In-vitro characterization of the cytochrome P450 isoenzymes involved in the back oxidation and N-dealkylation of reduced haloperidol. Pharmacogenetics 1998; 8: 383–9

    Article  PubMed  CAS  Google Scholar 

  169. Kim YH, Cha IJ, Shim JC, et al. Effect of rifampin on the plasma concentration and the clinical effect of haloperidol concomitantly administered to schizophrenic patients. J Clin Psychopharmacol 1996; 16: 247–52

    Article  PubMed  CAS  Google Scholar 

  170. Avenoso A, Spina E, Campo G, et al. Interaction between fluoxetine and haloperidol: pharmacokinetic and clinical implications. Pharmacol Res 1997; 35: 335–9

    PubMed  CAS  Google Scholar 

  171. Vandel S, Bertschy G, Baumann P, et al. Fluvoxamine and fluoxetine: interaction studies with amitriptyline, clomipramine and neuroleptics in phenotyped patients. Pharmacol Res 1995; 31: 347–53

    Article  PubMed  CAS  Google Scholar 

  172. Ulrich S, Wurthmann C, Brosz M, et al. The relationship between serum concentration and therapeutic effect of haloperidol in patients with acute schizophrenia. Clin Pharmacokinet 1998; 34: 227–63

    Article  PubMed  CAS  Google Scholar 

  173. Lane HY, Hu OY, Jann MW, et al. Dextromethorphan phenotyping and haloperidol disposition in schizophrenic patients. Psychiatry Res 1997; 69: 105–11

    Article  PubMed  CAS  Google Scholar 

  174. Llerena A, Alm C, Dahl ML, et al. Haloperidol disposition is dependent on debrisoquine hydroxylation phenotype. Ther Drug Monit 1992; 14: 92–7

    Article  PubMed  CAS  Google Scholar 

  175. Llerena A, Dahl ML, 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: 261–4

    Article  PubMed  CAS  Google Scholar 

  176. Nyberg S, Farde L, Halldin C, et al. D2 dopamine receptor occupancy during low-dose treatment with haloperidol decanoate. Am J Psychiatry 1995; 152: 173–8

    PubMed  CAS  Google Scholar 

  177. Brockmoller J, Kirchheiner J, Schmider J, et al. The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment. Clin Pharmacol Ther 2002; 72: 438–52

    Article  PubMed  CAS  Google Scholar 

  178. Panagiotidis G, Arthur HW, Lindh JD, et al. Depot haloperidol treatment in outpatients with schizophrenia on monotherapy: impact of CYP2D6 polymorphism on pharmacokinetics and treatment outcome. Ther Drug Monit 2007; 29: 417–22

    Article  PubMed  CAS  Google Scholar 

  179. Suzuki A, Otani K, Mihara K, et al. Effects of the CYP2D6 genotype on the steady-state plasma concentrations of haloperidol and reduced haloperidol in Japanese schizophrenic patients. Pharmacogenetics 1997; 7: 415–8

    Article  PubMed  CAS  Google Scholar 

  180. Mihara K, Suzuki A, Kondo T, et al. Effects of the CYP2D6*10 allele on the steady-state plasma concentrations of haloperidol and reduced haloperidol in Japanese patients with schizophrenia. Clin Pharmacol Ther 1999; 65: 291–4

    Article  PubMed  CAS  Google Scholar 

  181. Roh HK, Chung JY, Oh DY, et al. Plasma concentrations of haloperidol are related to CYP2D6 genotype at low, but not high doses of haloperidol in Korean schizophrenic patients. Br J Clin Pharmacol 2001; 52: 265–71

    Article  PubMed  CAS  Google Scholar 

  182. Park JY, Shon JH, Kim KA, et al. Combined effects of itraconazole and CYP2D6*10 genetic polymorphism on the pharmacokinetics and pharmacodynamics of haloperidol in healthy subjects. J Clin Psychopharmacol 2006; 26: 135–42

    Article  PubMed  CAS  Google Scholar 

  183. Shimoda K, Morita S, Yokono A, et al. CYP2D6*10 alleles are not the determinant of the plasma haloperidol concentrations in Asian patients. Ther Drug Monit 2000; 22: 392–6

    Article  PubMed  CAS  Google Scholar 

  184. Ohnuma T, Shibata N, Matsubara Y, et al. Haloperidol plasma concentration in Japanese psychiatric subjects with gene duplication of CYP2D6. Br J Clin Pharmacol 2003; 56: 315–20

    Article  PubMed  CAS  Google Scholar 

  185. Pan L, Vander Stichele R, Rosseel MT, et al. Effects of smoking, CYP2D6 genotype, and concomitant drug intake on the steady state plasma concentrations of haloperidol and reduced haloperidol in schizophrenic inpatients. Ther Drug Monit 1999; 21: 489–97

    Article  PubMed  CAS  Google Scholar 

  186. Someya T, Suzuki Y, Shimoda K, et al. The effect of cytochrome P450 2D6 genotypes on haloperidol metabolism: a preliminary study in a psychiatric population. Psychiatry Clin Neurosci 1999; 53: 593–7

    Article  PubMed  CAS  Google Scholar 

  187. Hartung B, Wada M, Laux G, et al. Perphenazine for schizophrenia. Cochrane Database Syst Rev 2005; (1): CD003443

    PubMed  Google Scholar 

  188. Olesen OV, Linnet K. Identification of the human cytochrome P450 isoforms mediating in vitro N-dealkylation of perphenazine. Br J Clin Pharmacol 2000; 50: 563–71

    Article  PubMed  CAS  Google Scholar 

  189. Bertilsson L, Dahl ML, Ekqvist B, et al. Disposition of the neuroleptics perphenazine, zuclopenthixol, and haloperidol cosegregates with polymorphic debrisoquine hydroxylation. Psychopharmacol Ser 1993; 10: 230–7

    PubMed  CAS  Google Scholar 

  190. Dahl-Puustinen ML, Liden A, Alm C, et al. Disposition of perphenazine is related to polymorphic debrisoquin hydroxylation in human beings. Clin Pharmacol Ther 1989; 46: 78–81

    Article  PubMed  CAS  Google Scholar 

  191. Linnet K, Wiborg O. Steady-state serum concentrations of the neuroleptic perphenazine in relation to CYP2D6 genetic polymorphism. Clin Pharmacol Ther 1996; 60: 41–7

    Article  PubMed  CAS  Google Scholar 

  192. Jerling M, Dahl ML, Aberg-Wistedt A, et al. The CYP2D6 genotype predicts the oral clearance of the neuroleptic agents perphenazine and zuclopenthixol. Clin Pharmacol Ther 1996; 59: 423–8

    Article  PubMed  CAS  Google Scholar 

  193. Ozdemir V, Bertilsson L, Miura J, et al. CYP2D6 genotype in relation to perphenazine concentration and pituitary pharmacodynamic tissue sensitivity in Asians: CYP2D6-serotonin-dopamine crosstalk revisited. Pharmacogenet Genomics 2007; 17: 339–47

    Article  PubMed  CAS  Google Scholar 

  194. Aklillu E, Kalow W, Endrenyi L, et al. CYP2D6 and DRD2 genes differentially impact pharmacodynamic sensitivity and time course of prolactin response to perphenazine. Pharmacogenet Genomics 2007; 17: 989–93

    Article  PubMed  CAS  Google Scholar 

  195. Bushe C, Shaw M, Peveler RC. A review of the association between antipsychotic use and hyperprolactinaemia. J Psychopharmacol 2008; 22: 46–55

    Article  PubMed  Google Scholar 

  196. O’Keane V. Antipsychotic-induced hyperprolactinaemia, hypogonadism and osteoporosis in the treatment of schizophrenia. J Psychopharmacol 2008; 22: 70–5

    Article  PubMed  Google Scholar 

  197. Peveler RC, Branford D, Citrome L, et al. Antipsychotics and hyperprolactinaemia: clinical recommendations. J Psychopharmacol 2008; 22: 98–103

    Article  PubMed  Google Scholar 

  198. Molitch ME. Drugs and prolactin. Pituitary 2008; 11: 209–18

    Article  PubMed  CAS  Google Scholar 

  199. Haddad PM, Wieck A. Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. Drugs 2004; 64: 2291–314

    Article  PubMed  CAS  Google Scholar 

  200. Yu AM, Idle JR, Byrd LG, et al. Regeneration of serotonin from 5-methoxytryptamine by polymorphic human CYP2D6. Pharmacogenetics 2003; 13: 173–81

    Article  PubMed  CAS  Google Scholar 

  201. Ozdemir V, Naranjo CA, Herrmann N, et al. Paroxetine potentiates the central nervous system side effects of perphenazine: contribution of cytochrome P4502D6 inhibition in vivo. Clin Pharmacol Ther 1997; 62: 334–47

    Article  PubMed  CAS  Google Scholar 

  202. Pollock BG, Mulsant BH, Sweet RA, et al. Prospective cytochrome P450 phenotyping for neuroleptic treatment in dementia. Psychopharmacol Bull 1995; 31: 327–31

    PubMed  CAS  Google Scholar 

  203. Fenton C, Scott LJ. Risperidone: a review of its use in the treatment of bipolar mania. CNS Drugs 2005; 19: 429–44

    Article  PubMed  CAS  Google Scholar 

  204. Grant S, Fitton A. Risperidone: a review of its pharmacology and therapeutic potential in the treatment of schizophrenia. Drugs 1994; 48: 253–73

    Article  PubMed  CAS  Google Scholar 

  205. Mannens G, Huang ML, Meuldermans W, et al. Absorption, metabolism, and excretion of risperidone in humans. Drug Metab Dispos 1993; 21: 1134–41

    PubMed  CAS  Google Scholar 

  206. Yasui-Furukori N, Hidestrand M, Spina E, et al. Different enantioselective 9-hydroxylation of risperidone by the two human CYP2D6 and CYP3A4 enzymes. Drug Metab Dispos 2001; 29: 1263–8

    PubMed  CAS  Google Scholar 

  207. Spina E, Avenoso A, Facciola G, et al. Plasma concentrations of risperidone and 9-hydroxyrisperidone: effect of comedication with carbamazepine or valproate. Ther Drug Monit 2000; 22: 481–5

    Article  PubMed  CAS  Google Scholar 

  208. Jung SM, Kim KA, Cho HK, et al. Cytochrome P450 3A inhibitor itraconazole affects plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients. Clin Pharmacol Ther 2005; 78: 520–8

    Article  PubMed  CAS  Google Scholar 

  209. Schotte A, Janssen PF, Gommeren W, et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl) 1996; 124: 57–73

    Article  CAS  Google Scholar 

  210. Spina E, Avenoso A, Facciola G, et al. Plasma concentrations of risperidone and 9-hydroxyrisperidone during combined treatment with paroxetine. Ther Drug Monit 2001; 23: 223–7

    Article  PubMed  CAS  Google Scholar 

  211. Mannheimer B, Bahr CV, Pettersson H, et al. Impact of multiple inhibitors or substrates of cytochrome P450 2D6 on plasma risperidone levels in patients on polypharmacy. Ther Drug Monit. Epub 2008 Aug 23

  212. Scordo MG, Spina E, Facciola G, et al. Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxyrisperidone. Psychopharmacology (Berl) 1999; 147: 300–5

    Article  CAS  Google Scholar 

  213. Bondolfi G, Eap CB, Bertschy G, et al. The effect of fluoxetine on the pharmacokinetics and safety of risperidone in psychotic patients. Pharmacopsychiatry 2002; 35: 50–6

    Article  PubMed  CAS  Google Scholar 

  214. Olesen OV, Licht RW, Thomsen E, et al. Serum concentrations and side effects in psychiatric patients during risperidone therapy. Ther Drug Monit 1998; 20: 380–4

    Article  PubMed  CAS  Google Scholar 

  215. Nyberg S, Dahl ML, Halldin C. A PET study of D2 and 5-HT2 receptor occupancy induced by risperidone in poor metabolizers of debrisoquin and risperidone. Psychopharmacology (Berl) 1995; 119: 345–8

    Article  CAS  Google Scholar 

  216. Roh HK, Kim CE, Chung WG, et al. Risperidone metabolism in relation to CYP2D6*10 allele in Korean schizophrenic patients. Eur J Clin Pharmacol 2001; 57: 671–5

    Article  PubMed  CAS  Google Scholar 

  217. Guzey C, Aamo T, Spigset O. Risperidone metabolism and the impact of being a cytochrome P450 2D6 ultrarapid metabolizer. J Clin Psychiatry 2000; 61: 600–1

    Article  PubMed  CAS  Google Scholar 

  218. De Leon J, Susce MT, Pan RM, et al. The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry 2005; 66: 15–27

    Article  PubMed  Google Scholar 

  219. Wojcikowski J, Maurel P, Daniel WA. Characterization of human cytochrome P450 enzymes involved in the metabolism of the piperidine-type phenothiazine neuroleptic thioridazine. Drug Metab Dispos 2006; 34: 471–6

    PubMed  CAS  Google Scholar 

  220. Llerena A, Berecz R, de la Rubia A, et al. Use of the mesoridazine/thioridazine ratio as a marker for CYP2D6 enzyme activity. Ther Drug Monit 2000; 22: 397–401

    Article  PubMed  CAS  Google Scholar 

  221. Berecz R, de la Rubia A, Dorado P, et al. Thioridazine steady-state plasma concentrations are influenced by tobacco smoking and CYP2D6, but not by the CYP2C9 genotype. Eur J Clin Pharmacol 2003; 59: 45–50

    PubMed  CAS  Google Scholar 

  222. Eap CB, Guentert TW, Schaublin-Loidl M, et al. Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizers of dextromethorphan and mephenytoin. Clin Pharmacol Ther 1996; 59: 322–31

    Article  PubMed  CAS  Google Scholar 

  223. Llerena A, Berecz R, de la Rubia A, et al. QTc interval lengthening is related to CYP2D6 hydroxylation capacity and plasma concentration of thioridazine in patients. J Psychopharmacol 2002; 16: 361–4

    Article  PubMed  CAS  Google Scholar 

  224. von Bahr C, Movin G, Nordin C, et al. Plasma levels of thioridazine and metabolites are influenced by the debrisoquin hydroxylation phenotype. Clin Pharmacol Ther 1991; 49: 234–40

    Article  Google Scholar 

  225. Kumar A, Strech D. Zuclopenthixol dihydrochloride for schizophrenia. Cochrane Database Syst Rev 2005; (4): CD005474

    PubMed  Google Scholar 

  226. Dahl ML, Ekqvist B, Widen J, et al. Disposition of the neuroleptic zuclopenthixol cosegregates with the polymorphic hydroxylation of debrisoquine in humans. Acta Psychiatr Scand 1991; 84: 99–102

    Article  PubMed  CAS  Google Scholar 

  227. Linnet K, Wiborg O. Influence of CYP2D6 genetic polymorphism on ratios of steady-state serum concentration to dose of the neuroleptic zuclopenthixol. Ther Drug Monit 1996; 18: 629–34

    Article  PubMed  CAS  Google Scholar 

  228. Jaanson P, Marandi T, Kiivet RA, et al. Maintenance therapy with zuclopenthixol decanoate: associations between plasma concentrations, neurological side effects and CYP2D6 genotype. Psychopharmacology (Berl) 2002; 162: 67–73

    Article  CAS  Google Scholar 

  229. Ring BJ, Catlow J, Lindsay TJ, et al. Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine. J Pharmacol Exp Ther 1996; 276: 658–66

    PubMed  CAS  Google Scholar 

  230. Olesen OV, Linnet K. Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. J Clin Pharmacol 2001; 41: 823–32

    Article  PubMed  CAS  Google Scholar 

  231. Schaber G, Wiatr G, Wachsmuth H, et al. Isolation and identification of clozapine metabolites in patient urine. Drug Metab Dispos 2001; 29: 923–31

    PubMed  CAS  Google Scholar 

  232. Breyer-Pfaff U, Wachsmuth H. Tertiary N-glucuronides of clozapine and its metabolite desmethylclozapine in patient urine. Drug Metab Dispos 2001; 29: 1343–8

    PubMed  CAS  Google Scholar 

  233. Hagg S, Spigset O, Lakso HA, et al. Olanzapine disposition in humans is unrelated to CYP1A2 and CYP2D6 phenotypes. Eur J Clin Pharmacol 2001; 57: 493–7

    Article  PubMed  CAS  Google Scholar 

  234. Carrillo JA, Herraiz AG, Ramos SI, et al. Role of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol 2003; 23: 119–27

    Article  PubMed  CAS  Google Scholar 

  235. Melkersson KI, Scordo MG, Gunes A, et al. Impact of CYP1A2 and CYP2D6 polymorphisms on drug metabolism and on insulin and lipid elevations and insulin resistance in clozapine-treated patients. J Clin Psychiatry 2007; 68: 697–704

    Article  PubMed  CAS  Google Scholar 

  236. Dettling M, Sachse C, Muller-Oerlinghausen B, et al. Clozapine-induced agranulocytosis and hereditary polymorphisms of clozapine metabolizing enzymes: no association with myeloperoxidase and cytochrome P4502D6. Pharmacopsychiatry 2000; 33: 218–20

    Article  PubMed  CAS  Google Scholar 

  237. Uehlinger C, Crettol S, Chassot P, et al. Increased (R)-methadone plasma concentrations by quetiapine in cytochrome P450s and ABCB1 genotyped patients. J Clin Psychopharmacol 2007; 27: 273–8

    Article  PubMed  CAS  Google Scholar 

  238. Plesnicar BK, Zalar B, Breskvar K, et al. The influence of the CYP2D6 polymorphism on psychopathological and extrapyramidal symptoms in the patients on long-term antipsychotic treatment. J Psychopharmacol 2006; 20: 829–33

    Article  PubMed  CAS  Google Scholar 

  239. Chou WH, Yan FX, de Leon J, et al. Extension of a pilot study: impact from the cytochrome P450 2D6 polymorphism on outcome and costs associated with severe mental illness. J Clin Psychopharmacol 2000; 20: 246–51

    Article  PubMed  CAS  Google Scholar 

  240. Dahl ML. Cytochrome P450 phenotyping/genotyping in patients receiving antipsychotics: useful aid to prescribing? Clin Pharmacokinet 2002; 41: 453–70

    Article  PubMed  CAS  Google Scholar 

  241. Otani K, Aoshima T. Pharmacogenetics of classical and new antipsychotic drugs. Ther Drug Monit 2000; 22: 118–21

    Article  PubMed  CAS  Google Scholar 

  242. Patsopoulos NA, Ntzani EE, Zintzaras E, et al. CYP2D6 polymorphisms and the risk of tardive dyskinesia in schizophrenia: a meta-analysis. Pharmacogenet Genomics 2005; 15: 151–8

    Article  PubMed  CAS  Google Scholar 

  243. Sjoqvist F, Eliasson E. The convergence of conventional therapeutic drug monitoring and pharmacogenetic testing in personalized medicine: focus on antidepressants. Clin Pharmacol Ther 2007; 81: 899–902

    Article  PubMed  CAS  Google Scholar 

  244. Jann MW, Shirley KL, Small GW. Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors. Clin Pharmacokinet 2002; 41: 719–39

    Article  PubMed  CAS  Google Scholar 

  245. Spaldin V, Madden S, Pool WF, et al. The effect of enzyme inhibition on the metabolism and activation of tacrine by human liver microsomes. Br J Clin Pharmacol 1994; 38: 15–22

    Article  PubMed  CAS  Google Scholar 

  246. Barner EL, Gray SL. Donepezil use in Alzheimer disease. Ann Pharmacother 1998; 32: 70–7

    Article  PubMed  CAS  Google Scholar 

  247. Bachus R, Bickel U, Thomsen T, et al. The O-demethylation of the antidementia drug galanthamine is catalysed by cytochrome P450 2D6. Pharmacogenetics 1999; 9: 661–8

    Article  PubMed  CAS  Google Scholar 

  248. Seltzer B. Donepezil: an update. Expert Opin Pharmacother 2007; 8: 1011–23

    Article  PubMed  CAS  Google Scholar 

  249. Varsaldi F, Miglio G, Scordo MG, et al. Impact of the CYP2D6 polymorphism on steady-state plasma concentrations and clinical outcome of donepezil in Alzheimer’s disease patients. Eur J Clin Pharmacol 2006; 62: 721–6

    Article  PubMed  CAS  Google Scholar 

  250. Whitehead A, Perdomo C, Pratt RD, et al. Donepezil for the symptomatic treatment of patients with mild to moderate Alzheimer’s disease: a metaanalysis of individual patient data from randomised controlled trials. Int J Geriatr Psychiatry 2004; 19: 624–33

    Article  PubMed  Google Scholar 

  251. Tiseo PJ, Perdomo CA, Friedhoff LT. Metabolism and elimination of 14C-donepezil in healthy volunteers: a single-dose study. Br J Clin Pharmacol 1998; 46 Suppl. 1: 19–24

    Article  PubMed  CAS  Google Scholar 

  252. Cacabelos R, Llovo R, Fraile C, et al. Pharmacogenetic aspects of therapy with cholinesterase inhibitors: the role of CYP2D6 in Alzheimer’s disease pharmacogenetics. Curr Alzheimer Res 2007; 4: 479–500

    Article  PubMed  CAS  Google Scholar 

  253. Pilotto A, Franceschi M, D’Onofrio G, et al. Effect of a CYP2D6 polymorphism on the efficacy of donepezil in patients with Alzheimer disease. Neurology 2009; 73: 761–7

    Article  PubMed  CAS  Google Scholar 

  254. Gaedigk A, Ryder DL, Bradford LD, et al. CYP2D6 poor metabolizer status can be ruled out by a single genotyping assay for the -1584G promoter polymorphism. Clin Chem 2003; 49: 1008–11

    Article  PubMed  CAS  Google Scholar 

  255. Kavirajan H, Schneider LS. Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials. Lancet Neurol 2007; 6: 782–92

    Article  PubMed  CAS  Google Scholar 

  256. Westra P, van Thiel MJ, Vermeer GA, et al. Pharmacokinetics of galanthamine (a long-acting anticholinesterase drug) in anaesthetized patients. Br J Anaesth 1986; 58: 1303–7

    Article  PubMed  CAS  Google Scholar 

  257. Mannens GS, Snel CA, Hendrickx J, et al. The metabolism and excretion of galantamine in rats, dogs, and humans. Drug Metab Dispos 2002; 30: 553–63

    Article  PubMed  CAS  Google Scholar 

  258. Corman SL, Fedutes BA, Culley CM. Atomoxetine: the first nonstimulant for the management of attention-deficit/hyperactivity disorder. Am J Health Syst Pharm 2004; 61: 2391–9

    PubMed  CAS  Google Scholar 

  259. Simpson D, Plosker GL. Atomoxetine: a review of its use in adults with attention deficit hyperactivity disorder. Drugs 2004; 64: 205–22

    Article  PubMed  CAS  Google Scholar 

  260. Ring BJ, Gillespie JS, Eckstein JA, et al. Identification of the human cytochromes P450 responsible for atomoxetine metabolism. Drug Metab Dispos 2002; 30: 319–23

    Article  PubMed  CAS  Google Scholar 

  261. Farid NA, Bergstrom RF, Ziege EA, et al. Single-dose and steady-state pharmacokinetics of tomoxetine in normal subjects. J Clin Pharmacol 1985; 25: 296–301

    PubMed  CAS  Google Scholar 

  262. Paulzen M, Clement HW, Grunder G. Enhancement of atomoxetine serum levels by co-administration of paroxetine. Int J Neuropsychopharmacol 2008; 11:289–91

    Article  PubMed  CAS  Google Scholar 

  263. Sauer JM, Ponsler GD, Mattiuz EL, et al. Disposition and metabolic fate of atomoxetine hydrochloride: the role of CYP2D6 in human disposition and metabolism. Drug Metab Dispos 2003; 31: 98–107

    Article  PubMed  CAS  Google Scholar 

  264. Cui YM, Teng CH, Pan AX, et al. Atomoxetine pharmacokinetics in healthy Chinese subjects and effect of the CYP2D6*10 allele. Br J Clin Pharmacol 2007; 64: 445–9

    Article  PubMed  CAS  Google Scholar 

  265. Shen H, He MM, Liu H, et al. Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17. Drug Metab Dispos 2007; 35: 1292–300

    Article  PubMed  CAS  Google Scholar 

  266. Michelson D, Read HA, Ruff DD, et al. CYP2D6 and clinical response to atomoxetine in children and adolescents with ADHD. J Am Acad Child Adolesc Psychiatry 2007; 46: 242–51

    Article  PubMed  Google Scholar 

  267. Trzepacz PT, Williams DW, Feldman PD, et al. CYP2D6 metabolizer status and atomoxetine dosing in children and adolescents with ADHD. Eur Neuropsychopharmacol 2008; 18: 79–86

    Article  PubMed  CAS  Google Scholar 

  268. Michelson D, Faries D, Wernicke J, et al. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. Pediatrics 2001; 108: E83

    Article  PubMed  CAS  Google Scholar 

  269. Wernicke JF, Kratochvil CJ. Safety profile of atomoxetine in the treatment of children and adolescents with ADHD. J Clin Psychiatry 2002; 63 Suppl. 12: 50–5

    PubMed  CAS  Google Scholar 

  270. Tamayo JM, Pumariega A, Rothe EM, et al. Latino versus Caucasian response to atomoxetine in attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 2008; 18: 44–53

    Article  PubMed  Google Scholar 

  271. Baskys A, Hou AC. Vascular dementia: pharmacological treatment approaches and perspectives. Clin Interv Aging 2007; 2: 327–35

    PubMed  CAS  Google Scholar 

  272. Winblad B, Fioravanti M, Dolezal T, et al. Therapeutic use of nicergoline. Clin Drug Investig 2008; 28: 533–52

    Article  PubMed  CAS  Google Scholar 

  273. Arcamone F, Glasser AG, Grafnetterova J, et al. Studies on the metabolism of ergoline derivatives: metabolism of nicergoline in man and in animals. Biochem Pharmacol 1972; 21: 2205–13

    Article  PubMed  CAS  Google Scholar 

  274. Bottiger Y, Dostert P, Benedetti MS, et al. Involvement of CYP2D6 but not CYP2C19 in nicergoline metabolism in humans. Br J Clin Pharmacol 1996; 42:707–11

    Article  PubMed  CAS  Google Scholar 

  275. Wefer J, Truss MC, Jonas U. Tolterodine: an overview. World J Urol 2001; 19: 312–8

    Article  PubMed  CAS  Google Scholar 

  276. Postlind H, Danielson A, Lindgren A, et al. Tolterodine, a new muscarinic receptor antagonist, is metabolized by cytochromes P450 2D6 and 3A in human liver microsomes. Drug Metab Dispos 1998; 26: 289–93

    PubMed  CAS  Google Scholar 

  277. Nilvebrant L, Gillberg PG, Sparf B. Antimuscarinic potency and bladder selectivity of PNU-200577, a major metabolite of tolterodine. Pharmacol Toxicol 1997; 81: 169–72

    Article  PubMed  CAS  Google Scholar 

  278. Brynne N, Forslund C, Hallen B, et al. Ketoconazole inhibits the metabolism of tolterodine in subjects with deficient CYP2D6 activity. Br J Clin Pharmacol 1999; 48: 564–72

    Article  PubMed  CAS  Google Scholar 

  279. Brynne N, Dalen P, Alvan G, et al. Influence of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamic of tolterodine. Clin Pharmacol Ther 1998; 63: 529–39

    Article  PubMed  CAS  Google Scholar 

  280. Brynne N, Bottiger Y, Hallen B, et al. Tolterodine does not affect the human in vivo metabolism of the probe drugs caffeine, debrisoquine and omeprazole. Br J Clin Pharmacol 1999; 47: 145–50

    Article  PubMed  CAS  Google Scholar 

  281. Brynne N, Svanstrom C, Aberg-Wistedt A, et al. Fluoxetine inhibits the metabolism of tolterodine-pharmacokinetic implications and proposed clinical relevance. Br J Clin Pharmacol 1999; 48: 553–63

    Article  PubMed  CAS  Google Scholar 

  282. Olsson B, Szamosi J. Food does not influence the pharmacokinetics of a new extended release formulation of tolterodine for once daily treatment of patients with overactive bladder. Clin Pharmacokinet 2001; 40: 135–43

    Article  PubMed  CAS  Google Scholar 

  283. Olsson B, Szamosi J. Multiple dose pharmacokinetics of a new once daily extended release tolterodine formulation versus immediate release tolterodine. Clin Pharmacokinet 2001; 40: 227–35

    Article  PubMed  CAS  Google Scholar 

  284. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med 2008; 358: 2482–94

    Article  PubMed  CAS  Google Scholar 

  285. Schwartzberg LS. Chemotherapy-induced nausea and vomiting: which antiemetic for which therapy? Oncology (Williston Park) 2007; 21: 946–53; discussion 954, 959, 962 passim

    Google Scholar 

  286. Aapro M. 5-HT3-receptor antagonists in the management of nausea and vomiting in cancer and cancer treatment. Oncology 2005; 69: 97–109

    Article  PubMed  CAS  Google Scholar 

  287. Aapro M, Blower P. 5-Hydroxytryptamine type-3 receptor antagonists for chemotherapy-induced and radiotherapy-induced nausea and emesis: can we safely reduce the dose of administered agents? Cancer 2005; 104: 1–18

    Article  PubMed  CAS  Google Scholar 

  288. Evangelista S. Eziopitant: Pfizer. Curr Opin Investig Drugs 2001; 2: 1441–3

    PubMed  CAS  Google Scholar 

  289. Fischer V, Baldeck JP, Tse FL. Pharmacokinetics and metabolism of the 5-hydroxytryptamine antagonist tropisetron after single oral doses in humans. Drug Metab Dispos 1992; 20: 603–7

    PubMed  CAS  Google Scholar 

  290. Kutz K. Pharmacology, toxicology and human pharmacokinetics of tropisetron. Ann Oncol 1993; 4 Suppl. 3: 15–18

    Article  PubMed  Google Scholar 

  291. Fischer V, Vickers AE, Heitz F, et al. The polymorphic cytochrome P-4502D6 is involved in the metabolism of both 5-hydroxytryptamine antagonists, tropisetron and ondansetron. Drug Metab Dispos 1994; 22: 269–74

    PubMed  CAS  Google Scholar 

  292. Sanwald P, David M, Dow J. Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of dolasetron: comparison with other indole-containing 5-HT3 antagonists. Drug Metab Dispos 1996; 24: 602–9

    PubMed  CAS  Google Scholar 

  293. Obach RS. Cytochrome P450-catalyzed metabolism of ezlopitant alkene (CJ-12,458), a pharmacologically active metabolite of ezlopitant: enzyme kinetics and mechanism of an alkene hydration reaction. Drug Metab Dispos 2001; 29: 1057–67

    PubMed  CAS  Google Scholar 

  294. Desta Z, Wu GM, Morocho AM, et al. The gastroprokinetic and antiemetic drug metoclopramide is a substrate and inhibitor of cytochrome P450 2D6. Drug Metab Dispos 2002; 30: 336–43

    Article  PubMed  CAS  Google Scholar 

  295. Gregory RE, Ettinger DS. 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting: a comparison of their pharmacology and clinical efficacy. Drugs 1998; 55: 173–89

    Article  PubMed  CAS  Google Scholar 

  296. Obach RS. Metabolism of ezlopitant, a nonpeptidic substance P receptor antagonist, in liver microsomes: enzyme kinetics, cytochrome P450 isoform identity, and in vitro-in vivo correlation. Drug Metab Dispos 2000; 28: 1069–76

    PubMed  CAS  Google Scholar 

  297. Sanchez RI, Wang RW, Newton DJ, et al. Cytochrome P450 3A4 is the major enzyme involved in the metabolism of the substance P receptor antagonist aprepitant. Drug Metab Dispos 2004; 32: 1287–92

    Article  PubMed  CAS  Google Scholar 

  298. Balfour JA, Goa KL. Dolasetron: a review of its pharmacology and therapeutic potential in the management of nausea and vomiting induced by chemotherapy, radiotherapy or surgery. Drugs 1997; 54: 273–98

    Article  PubMed  CAS  Google Scholar 

  299. Reith MK, Sproles GD, Cheng LK. Human metabolism of dolasetron mesylate, a 5-HT3 receptor antagonist. Drug Metab Dispos 1995; 23: 806–12

    PubMed  CAS  Google Scholar 

  300. Janicki PK, Schuler HG, Jarzembowski TM, et al. Prevention of postoperative nausea and vomiting with granisetron and dolasetron in relation to CYP2D6 genotype. Anesth Analg 2006; 102: 1127–33

    Article  PubMed  CAS  Google Scholar 

  301. Milne RJ, Heel RC. Ondansetron: therapeutic use as an antiemetic. Drugs 1991; 41: 574–95

    Article  PubMed  CAS  Google Scholar 

  302. Ashforth EI, Palmer JL, Bye A, et al. The pharmacokinetics of ondansetron after intravenous injection in healthy volunteers phenotyped as poor or extensive metabolisers of debrisoquine. Br J Clin Pharmacol 1994; 37: 389–91

    Article  PubMed  CAS  Google Scholar 

  303. Candiotti KA, Birnbach DJ, Lubarsky DA, et al. The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? Anesthesiology 2005; 102: 543–9

    Article  PubMed  CAS  Google Scholar 

  304. Simpson K, Spencer CM, McClellan KJ. Tropisetron: an update of its use in the prevention of chemotherapy-induced nausea and vomiting. Drugs 2000; 59: 1297–315

    Article  PubMed  CAS  Google Scholar 

  305. Lee CR, Plosker GL, McTavish D. Tropisetron: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential as an antiemetic. Drugs 1993; 46: 925–43

    Article  PubMed  CAS  Google Scholar 

  306. Firkusny L, Kroemer HK, Eichelbaum M. In vitro characterization of cytochrome P450 catalysed metabolism of the antiemetic tropisetron. Biochem Pharmacol 1995; 49: 1777–84

    Article  PubMed  CAS  Google Scholar 

  307. Kim MK, Cho JY, Lim HS, et al. Effect of the CYP2D6 genotype on the pharmacokinetics of tropisetron in healthy Korean subjects. Eur J Clin Pharmacol 2003; 59: 111–6

    PubMed  CAS  Google Scholar 

  308. Kaiser R, Sezer O, Papies A, et al. Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes. J Clin Oncol 2002; 20: 2805–11

    Article  PubMed  CAS  Google Scholar 

  309. Oppenheimer JJ, Casale TB. Next generation antihistamines: therapeutic rationale, accomplishments and advances. Expert Opin Investig Drugs 2002; 11: 807–17

    Article  PubMed  CAS  Google Scholar 

  310. Devillier P, Roche N, Faisy C. Clinical pharmacokinetics and pharmacodynamics of desloratadine, fexofenadine and levocetirizine: a comparative review. Clin Pharmacokinet 2008; 47: 217–30

    Article  PubMed  CAS  Google Scholar 

  311. Yumibe N, Huie K, Chen KJ, et al. Identification of human liver cytochrome P450 enzymes that metabolize the nonsedating antihistamine loratadine: formation of descarboethoxyloratadine by CYP3A4 and CYP2D6. Biochem Pharmacol 1996; 51: 165–72

    Article  PubMed  CAS  Google Scholar 

  312. Yumibe N, Huie K, Chen KJ, et al. Identification of human liver cytochrome P450s involved in the microsomal metabolism of the antihistaminic drug loratadine. Int Arch Allergy Immunol 1995; 107: 420

    Article  PubMed  CAS  Google Scholar 

  313. Nakamura K, Yokoi T, Inoue K, et al. CYP2D6 is the principal cytochrome P450 responsible for metabolism of the histamine H1 antagonist promethazine in human liver microsomes. Pharmacogenetics 1996; 6: 449–57

    Article  PubMed  CAS  Google Scholar 

  314. Matsumoto S, Yamazoe Y. Involvement of multiple human cytochromes P450 in the liver microsomal metabolism of astemizole and a comparison with terfenadine. Br J Clin Pharmacol 2001; 51: 133–42

    PubMed  CAS  Google Scholar 

  315. Nakamura K, Yokoi T, Kodama T, et al. Oxidation of histamine H1 antagonist mequitazine is catalyzed by cytochrome P450 2D6 in human liver microsomes. J Pharmacol Exp Ther 1998; 284: 437–42

    PubMed  CAS  Google Scholar 

  316. Jones BC, Hyland R, Ackland M, et al. Interaction of terfenadine and its primary metabolites with cytochrome P450 2D6. Drug Metab Dispos 1998; 26: 875–82

    PubMed  CAS  Google Scholar 

  317. Imai T, Taketani M, Suzu T, et al. In vitro identification of the human cytochrome P-450 enzymes involved in the N-demethylation of azelastine. Drug Metab Dispos 1999; 27: 942–6

    PubMed  CAS  Google Scholar 

  318. Nakajima M, Nakamura S, Tokudome S, et al. Azelastine N-demethylation by cytochrome P-450 (CYP)3A4, CYP2D6, and CYP1A2 in human liver microsomes: evaluation of approach to predict the contribution of multiple CYPs. Drug Metab Dispos 1999; 27: 1381–91

    PubMed  CAS  Google Scholar 

  319. Goto A, Ueda K, Inaba A, et al. Identification of human P450 isoforms involved in the metabolism of the antiallergic drug, oxatomide, and its kinetic parameters and inhibition constants. Biol Pharm Bull 2005; 28: 328–34

    Article  PubMed  CAS  Google Scholar 

  320. Goto A, Adachi Y, Inaba A, et al. Identification of human P450 isoforms involved in the metabolism of the antiallergic drug, oxatomide, and its inhibitory effect on enzyme activity. Biol Pharm Bull 2004; 27: 684–90

    Article  PubMed  CAS  Google Scholar 

  321. Kishimoto W, Hiroi T, Sakai K, et al. Metabolism of epinastine, a histamine H1 receptor antagonist, in human liver microsomes in comparison with that of terfenadine. Res Commun Mol Pathol Pharmacol 1997; 98: 273–92

    PubMed  CAS  Google Scholar 

  322. Narimatsu S, Kariya S, Isozaki S, et al. Involvement of CYP2D6 in oxidative metabolism of cinnarizine and flunarizine in human liver microsomes. Biochem Biophys Res Commun 1993; 193: 1262–8

    Article  PubMed  CAS  Google Scholar 

  323. Kariya S, Isozaki S, Uchino K, et al. Oxidative metabolism of flunarizine and cinnarizine by microsomes from B-lymphoblastoid cell lines expressing human cytochrome P450 enzymes. Biol Pharm Bull 1996; 19: 1511–4

    Article  PubMed  CAS  Google Scholar 

  324. Akutsu T, Kobayashi K, Sakurada K, et al. Identification of human cytochrome P450 isozymes involved in diphenhydramine N-demethylation. Drug Metab Dispos 2007; 35: 72–8

    Article  PubMed  CAS  Google Scholar 

  325. He N, Zhang WQ, Shockley D, et al. Inhibitory effects of H1-antihistamines on CYP2D6- and CYP2C9-mediated drug metabolic reactions in human liver microsomes. Eur J Clin Pharmacol 2002; 57: 847–51

    Article  PubMed  CAS  Google Scholar 

  326. Yasuda SU, Zannikos P, Young AE, et al. The roles of CYP2D6 and stereoselectivity in the clinical pharmacokinetics of chlorpheniramine. Br J Clin Pharmacol 2002; 53: 519–25

    Article  PubMed  CAS  Google Scholar 

  327. Tran VT, Chang RS, Snyder SH. Histamine H1. receptors identified in mammalian brain membranes with [3H]mepyramine. Proc Natl Acad Sci USA 1978; 75: 6290–4

    Article  PubMed  CAS  Google Scholar 

  328. Peets EA, Jackson M, Symchowicz S. Metabolism of chlorpheniramine maleate in man. J Pharmacol Exp Ther 1972; 180: 364–74

    PubMed  CAS  Google Scholar 

  329. Yasuda SU, Wellstein A, Likhari P, et al. Chlorpheniramine plasma concentration and histamine H1-receptor occupancy. Clin Pharmacol Ther 1995; 58: 210–20

    Article  PubMed  CAS  Google Scholar 

  330. Banerji A, Long AA, Camargo CA, et al. Diphenhydramine versus nonsedating antihistamines for acute allergic reactions: a literature review. Allergy Asthma Proc 2007; 28: 418–26

    Article  PubMed  CAS  Google Scholar 

  331. McGeer PL, Boulding JE, Gibson WC, et al. Drug-induced extrapyramidal reactions: treatment with diphenhydramine hydrochloride and dihydroxyphenylalanine. JAMA 1961; 177: 665–70

    Article  PubMed  CAS  Google Scholar 

  332. Chang T, Okerholm RA, Glazko AJ. Identification of diphenydramine (Benadryl) metabolities in human subjects. Res Commun Chem Pathol Pharmacol 1974; 9: 391–404

    PubMed  CAS  Google Scholar 

  333. Blyden GT, Greenblatt DJ, Scavone JM, et al. Pharmacokinetics of diphenhydramine and a demethylated metabolite following intravenous and oral administration. J Clin Pharmacol 1986; 26: 529–33

    PubMed  CAS  Google Scholar 

  334. Sharma A, Hamelin BA. Classic histamine H1 receptor antagonists: a critical review of their metabolic and pharmacokinetic fate from a bird’s eye view. Curr Drug Metab 2003; 4: 105–29

    Article  PubMed  CAS  Google Scholar 

  335. Breyer-Pfaff U, Fischer D, Winne D. Biphasic kinetics of quaternary ammonium glucuronide formation from amitriptyline and diphenhydramine in human liver microsomes. Drug Metab Dispos 1997; 25: 340–5

    PubMed  CAS  Google Scholar 

  336. Fischer D, Breyer-Pfaff U. Variability of diphenhydramine N-glucuronidation in healthy subjects. Eur J Drug Metab Pharmacokinet 1997; 22: 151–4

    Article  PubMed  CAS  Google Scholar 

  337. Luo H, Hawes EM, McKay G, et al. N+-glucuronidation of aliphatic tertiary amines, a general phenomenon in the metabolism of H1-antihistamines in humans. Xenobiotica 1991; 21: 1281–8

    Article  PubMed  CAS  Google Scholar 

  338. Lessard E, Yessine MA, Hamelin BA, et al. Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans. J Clin Psychopharmacol 2001; 21: 175–84

    Article  PubMed  CAS  Google Scholar 

  339. Haria M, Fitton A, Peters DH. Loratadine: a reappraisal of its pharmacological properties and therapeutic use in allergic disorders. Drugs 1994; 48: 617–37

    Article  PubMed  CAS  Google Scholar 

  340. Ramanathan R, Reyderman L, Su AD, et al. Disposition of desloratadine in healthy volunteers. Xenobiotica 2007; 37: 770–87

    Article  PubMed  CAS  Google Scholar 

  341. Ramanathan R, Reyderman L, Kulmatycki K, et al. Disposition of loratadine in healthy volunteers. Xenobiotica 2007; 37: 753–69

    Article  PubMed  CAS  Google Scholar 

  342. Yin OQ, Shi XJ, Tomlinson B, et al. Effect of CYP2D6*10 allele on the pharmacokinetics of loratadine in Chinese subjects. Drug Metab Dispos 2005; 33: 1283–7

    Article  PubMed  CAS  Google Scholar 

  343. Saruwatari J, Matsunaga M, Ikeda K, et al. Impact of CYP2D6*10 on H1-antihistamine-induced hypersomnia. Eur J Clin Pharmacol 2006; 62: 995–1001

    Article  PubMed  CAS  Google Scholar 

  344. Lotsch J. Opioid metabolites. J Pain Symptom Manage 2005; 29: S10–24

    Article  PubMed  CAS  Google Scholar 

  345. Dayer P, Desmeules J, Leemann T, et al. Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation (cytochrome P-450 dbl/bufI). Biochem Biophys Res Commun 1988; 152: 411–6

    Article  PubMed  CAS  Google Scholar 

  346. Yue QY, Sawe J. Different effects of inhibitors on the O- and N-demethylation of codeine in human liver microsomes. Eur J Clin Pharmacol 1997; 52: 41–7

    Article  PubMed  CAS  Google Scholar 

  347. Ohno S, Kawana K, Nakajin S. Contribution of UDP-glucuronosyltransferase 1A1 and 1A8 to morphine-6-glucuronidation and its kinetic properties. Drug Metab Dispos 2008; 36: 688–94

    Article  PubMed  CAS  Google Scholar 

  348. Lotsch J, Skarke C, Liefhold J, et al. Genetic predictors of the clinical response to opioid analgesics: clinical utility and future perspectives. Clin Pharmacokinet 2004; 43: 983–1013

    Article  PubMed  Google Scholar 

  349. Eckhardt K, Li S, Ammon S, et al. Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. Pain 1998; 76: 27–33

    Article  PubMed  CAS  Google Scholar 

  350. Poulsen L, Brosen K, Arendt-Nielsen L, et al. Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects. Eur J Clin Pharmacol 1996; 51: 289–95

    Article  PubMed  CAS  Google Scholar 

  351. Caraco Y, Sheller J, Wood AJ. Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. J Pharmacol Exp Ther 1996; 278: 1165–74

    PubMed  CAS  Google Scholar 

  352. Tyndale RF, Droll KP, Sellers EM. Genetically deficient CYP2D6 metabolism provides protection against oral opiate dependence. Pharmacogenetics 1997; 7: 375–9

    Article  PubMed  CAS  Google Scholar 

  353. Mikus G, Bochner F, Eichelbaum M, et al. Endogenous codeine and morphine in poor and extensive metabolisers of the CYP2D6 (debrisoquine/sparteine) polymorphism. J Pharmacol Exp Ther 1994; 268: 546–51

    PubMed  CAS  Google Scholar 

  354. Mikus G, Morike K, Griese EU, et al. Relevance of deficient CYP2D6 in opiate dependence. Pharmacogenetics 1998; 8: 565–8

    Article  PubMed  CAS  Google Scholar 

  355. Somogyi AA, Barratt DT, Coller JK. Pharmacogenetics of opioids. Clin Pharmacol Ther 2007; 81: 429–44

    Article  PubMed  CAS  Google Scholar 

  356. Koren G, Cairns J, Chitayat D, et al. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 2006; 368: 704

    Article  PubMed  Google Scholar 

  357. Madadi P, Ross CJ, Hayden MR, et al. Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a casecontrol study. Clin Pharmacol Ther 2009; 85: 31–5

    Article  PubMed  CAS  Google Scholar 

  358. Edwards JE, McQuay HJ, Moore RA. Single dose dihydrocodeine for acute postoperative pain. Cochrane Database Syst Rev 2000; (4): CD002760

    PubMed  Google Scholar 

  359. Kirkwood LC, Nation RL, Somogyi AA. Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine. Br J Clin Pharmacol 1997; 44: 549–55

    Article  PubMed  CAS  Google Scholar 

  360. Fromm MF, Hofmann U, Griese EU, et al. Dihydrocodeine: a new opioid substrate for the polymorphic CYP2D6 in humans. Clin Pharmacol Ther 1995; 58: 374–82

    Article  PubMed  CAS  Google Scholar 

  361. Wilder-Smith CH, Hufschmid E, Thormann W. The visceral and somatic antinociceptive effects of dihydrocodeine and its metabolite, dihydromorphine: a cross-over study with extensive and quinidine-induced poor metabolizers. Br J Clin Pharmacol 1998; 45: 575–81

    Article  PubMed  CAS  Google Scholar 

  362. Schmidt H, Vormfelde SV, Walchner-Bonjean M, et al. The role of active metabolites in dihydrocodeine effects. Int J Clin Pharmacol Ther 2003; 41: 95–106

    PubMed  CAS  Google Scholar 

  363. Chen ZR, Irvine RJ, Somogyi AA, et al. Mu receptor binding of some commonly used opioids and their metabolites. Life Sci 1991; 48: 2165–71

    Article  PubMed  CAS  Google Scholar 

  364. Hutchinson MR, Menelaou A, Foster DJ, et al. CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. Br J Clin Pharmacol 2004; 57: 287–97

    Article  PubMed  CAS  Google Scholar 

  365. Otton SV, Schadel M, Cheung SW, et al. CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone. Clin Pharmacol Ther 1993; 54: 463–72

    Article  PubMed  CAS  Google Scholar 

  366. Lelas S, Wegert S, Otton SV, et al. Inhibitors of cytochrome P450 differentially modify discriminative-stimulus and antinociceptive effects of hydrocodone and hydromorphone in rhesus monkeys. Drug Alcohol Depend 1999; 54: 239–49

    Article  PubMed  CAS  Google Scholar 

  367. Kaplan HL, Busto UE, Baylon GJ, et al. Inhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability. J Pharmacol Exp Ther 1997; 281: 103–8

    PubMed  CAS  Google Scholar 

  368. Poyhia R, Vainio A, Kalso E. A review of oxycodone’s clinical pharmacokinetics and pharmacodynamics. J Pain Symptom Manage 1993; 8: 63–7

    Article  PubMed  CAS  Google Scholar 

  369. Leow KP, Smith MT, Williams B, et al. Single-dose and steady-state pharmacokinetics and pharmacodynamics of oxycodone in patients with cancer. Clin Pharmacol Ther 1992; 52: 487–95

    Article  PubMed  CAS  Google Scholar 

  370. Lalovic B, Phillips B, Risler LL, et al. Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos 2004; 32: 447–54

    Article  PubMed  CAS  Google Scholar 

  371. Otton SV, Wu D, Joffe RT, et al. Inhibition by fluoxetine of cytochrome P450 2D6 activity. Clin Pharmacol Ther 1993; 53: 401–9

    Article  PubMed  CAS  Google Scholar 

  372. Heiskanen T, Olkkola KT, Kalso E. Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. Clin Pharmacol Ther 1998;64:603–11

    Article  PubMed  CAS  Google Scholar 

  373. Garrido MJ, Troconiz IF. Methadone: a review of its pharmacokinetic/ pharmacodynamic properties. J Pharmacol Toxicol Methods 1999; 42: 61–6

    Article  PubMed  CAS  Google Scholar 

  374. Kristensen K, Christensen CB, Christrup LL. The μ1, μ2, δ, Κ opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci 1995; 56: PL45–50

    Article  PubMed  CAS  Google Scholar 

  375. de Vos JW, Geerlings PJ, van den Brink W, et al. Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts. Eur J Clin Pharmacol 1995; 48: 361–6

    Article  PubMed  Google Scholar 

  376. Wang JS, DeVane CL. Involvement of CYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro. Drug Metab Dispos 2003; 31: 742–7

    Article  PubMed  CAS  Google Scholar 

  377. Coller JK, Joergensen C, Foster DJ, et al. Lack of influence of CYP2D6 genotype on the clearance of (R)-, (S)- and racemic-methadone. Int J Clin Pharmacol Ther 2007; 45: 410–7

    PubMed  CAS  Google Scholar 

  378. Crettol S, Deglon JJ, Besson J, et al. ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment. Clin Pharmacol Ther 2006; 80: 668–81

    Article  PubMed  CAS  Google Scholar 

  379. Shiran MR, Chowdry J, Rostami-Hodjegan A, et al. A discordance between cytochrome P450 2D6 genotype and phenotype in patients undergoing methadone maintenance treatment. Br J Clin Pharmacol 2003; 56: 220–4

    Article  PubMed  CAS  Google Scholar 

  380. Wu D, Otton SV, Sproule BA, et al. Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone. Br J Clin Pharmacol 1993; 35: 30–4

    Article  PubMed  CAS  Google Scholar 

  381. Begre S, von Bardeleben U, Ladewig D, et al. Paroxetine increases steadystate concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers. J Clin Psychopharmacol 2002; 22: 211–5

    Article  PubMed  CAS  Google Scholar 

  382. Eap CB, Bertschy G, Powell K, et al. Fluvoxamine and fluoxetine do not interact in the same way with the metabolism of the enantiomers of methadone. J Clin Psychopharmacol 1997; 17: 113–7

    Article  PubMed  CAS  Google Scholar 

  383. Cobb MN, Desai J, Brown Jr LS, et al. The effect of fluconazole on the clinical pharmacokinetics of methadone. Clin Pharmacol Ther 1998; 63: 655–62

    Article  PubMed  CAS  Google Scholar 

  384. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet 2004; 43: 879–923

    Article  PubMed  CAS  Google Scholar 

  385. Paar WD, Poche S, Gerloff J, et al. Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol. Eur J Clin Pharmacol 1997; 53: 235–9

    Article  PubMed  CAS  Google Scholar 

  386. Subrahmanyam V, Renwick AB, Walters DG, et al. Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos 2001; 29: 1146–55

    PubMed  CAS  Google Scholar 

  387. Abdel-Rahman SM, Leeder JS, Wilson JT, et al. Concordance between tramadol and dextromethorphan parent/metabolite ratios: the influence of CYP2D6 and non-CYP2D6 pathways on biotransformation. J Clin Pharmacol 2002; 42: 24–9

    Article  PubMed  CAS  Google Scholar 

  388. Poulsen L, Arendt-Nielsen L, Brosen K, et al. The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 1996; 60: 636–44

    Article  PubMed  CAS  Google Scholar 

  389. Enggaard TP, Poulsen L, Arendt-Nielsen L, et al. The analgesic effect of tramadol after intravenous injection in healthy volunteers in relation to CYP2D6. Anesth Analg 2006; 102: 146–50

    Article  PubMed  CAS  Google Scholar 

  390. Slanar O, Nobilis M, Kvetina J, et al. Miotic action of tramadol is determined by CYP2D6 genotype. Physiol Res 2007; 56: 129–36

    PubMed  CAS  Google Scholar 

  391. Fliegert F, Kurth B, Gohler K. The effects of tramadol on static and dynamic pupillometry in healthy subjects: the relationship between pharmacodynamics, pharmacokinetics and CYP2D6 metaboliser status. Eur J Clin Pharmacol 2005; 61: 257–66

    Article  PubMed  CAS  Google Scholar 

  392. Wang G, Zhang H, He F, et al. Effect of the CYP2D6*10 C188T polymorphism on postoperative tramadol analgesia in a Chinese population. Eur J Clin Pharmacol 2006; 62: 927–31

    Article  PubMed  CAS  Google Scholar 

  393. Gan SH, Ismail R, Wan Adnan WA, et al. Population pharmacokinetic modelling of tramadol with application of the NPEM algorithms. J Clin Pharm Ther 2004; 29: 455–63

    Article  PubMed  CAS  Google Scholar 

  394. Halling J, Weihe P, Brosen K. CYP2D6 polymorphism in relation to tramadol metabolism: a study of Faroese patients. Ther Drug Monit 2008; 30: 271–5

    Article  PubMed  CAS  Google Scholar 

  395. Gan SH, Ismail R, Wan Adnan WA, et al. Impact of CYP2D6 genetic polymorphism on tramadol pharmacokinetics and pharmacodynamics. Mol Diagn Ther 2007; 11: 171–81

    Article  PubMed  CAS  Google Scholar 

  396. Pedersen RS, Damkier P, Brosen K. Tramadol as a new probe for cytochrome P450 2D6 phenotyping: a population study. Clin Pharmacol Ther 2005; 77: 458–67

    Article  PubMed  CAS  Google Scholar 

  397. Pedersen RS, Damkier P, Brosen K. Enantioselective pharmacokinetics of tramadol in CYP2D6 extensive and poor metabolizers. Eur J Clin Pharmacol 2006; 62: 513–21

    Article  PubMed  CAS  Google Scholar 

  398. Garcia-Quetglas E, Azanza JR, Sadaba B, et al. Pharmacokinetics of tramadol enantiomers and their respective phase I metabolites in relation to CYP2D6 phenotype. Pharmacol Res 2007; 55: 122–30

    Article  PubMed  CAS  Google Scholar 

  399. Stamer UM, Lehnen K, Hothker F, et al. Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain 2003; 105: 231–8

    Article  PubMed  CAS  Google Scholar 

  400. Dalen P, Frengell C, Dahl ML, et al. Quick onset of severe abdominal pain after codeine in an ultrarapid metabolizer of debrisoquine. Ther Drug Monit 1997; 19: 543–4

    Article  PubMed  CAS  Google Scholar 

  401. De Leon J, Dinsmore L, Wedlund P. Adverse drug reactions to oxycodone and hydrocodone in CYP2D6 ultrarapid metabolizers. J Clin Psychopharmacol 2003; 23: 420–1

    Article  PubMed  Google Scholar 

  402. Kirchheiner J, Keulen JT, Bauer S, et al. Effects of the CYP2D6 gene duplication on the pharmacokinetics and pharmacodynamics of tramadol. J Clin Psychopharmacol 2008; 28: 78–83

    Article  PubMed  CAS  Google Scholar 

  403. Marchetti P, Giannarelli R, di Carlo A, et al. Pharmacokinetic optimisation of oral hypoglycaemic therapy. Clin Pharmacokinet 1991; 21: 308–17

    Article  PubMed  CAS  Google Scholar 

  404. Marchetti P, Navalesi R. Pharmacokinetic-pharmacodynamic relationships of oral hypoglycaemic agents. An update. Clin Pharmacokinet 1989; 16: 100–28

    Article  PubMed  CAS  Google Scholar 

  405. Oates NS, Shah RR, Idle JR, et al. Genetic polymorphism of phenformin 4-hydroxylation. Clin Pharmacol Ther 1982; 32: 81–9

    Article  PubMed  CAS  Google Scholar 

  406. Shah RR, Evans DA, Oates NS, et al. The genetic control of phenformin 4-hydroxylation. J Med Genet 1985; 22: 361–6

    Article  PubMed  Google Scholar 

  407. Shah RR, Oates NS, Idle JR, et al. Genetic impairment of phenformin metabolism. Lancet 1980; 1: 1147

    Article  PubMed  CAS  Google Scholar 

  408. Krentz AJ, Ferner RE, Bailey CJ. Comparative tolerability profiles of oral antidiabetic agents. Drug Saf 1994; 11: 223–41

    Article  PubMed  CAS  Google Scholar 

  409. Oates NS, Shah RR, Idle JR, et al. Influence of oxidation polymorphism on phenformin kinetics and dynamics. Clin Pharmacol Ther 1983; 34: 827–34

    Article  PubMed  CAS  Google Scholar 

  410. Oates NS, Shah RR, Idle JR, et al. Phenformin-induced lacticacidosis associated with impaired debrisoquine hydroxylation. Lancet 1981; 1: 837–8

    Article  PubMed  CAS  Google Scholar 

  411. Wiholm BE, Alvan G, Bertilsson L, et al. Hydroxylation of debrisoquine in patients with lacticacidosis after phenformin. Lancet 1981; 1: 1098–9

    Article  PubMed  CAS  Google Scholar 

  412. Sengupta S, Jordan VC. Selective estrogen modulators as an anticancer tool: mechanisms of efficiency and resistance. Adv Exp Med Biol 2008; 630: 206–19

    Article  PubMed  CAS  Google Scholar 

  413. Riggs BL, Hartmann LC. Selective estrogen-receptor modulators-mechanisms of action and application to clinical practice. N Engl J Med 2003; 348: 618–29

    Article  PubMed  CAS  Google Scholar 

  414. Jordan VC, O’Malley BW. Selective estrogen-receptor modulators and antihormonal resistance in breast cancer. J Clin Oncol 2007; 25: 5815–24

    Article  PubMed  CAS  Google Scholar 

  415. Jordan VC. Chemoprevention of breast cancer with selective oestrogenreceptor modulators. Nat Rev Cancer 2007; 7: 46–53

    Article  PubMed  CAS  Google Scholar 

  416. Desta Z, Ward BA, Soukhova NV, et al. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther 2004; 310: 1062–75

    Article  PubMed  CAS  Google Scholar 

  417. Beverage JN, Sissung TM, Sion AM, et al. CYP2D6 polymorphisms and the impact on tamoxifen therapy. J Pharm Sci 2007; 96: 2224–31

    Article  PubMed  CAS  Google Scholar 

  418. Stearns V, Johnson MD, Rae JM, et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 2003; 95: 1758–64

    Article  PubMed  CAS  Google Scholar 

  419. Crewe HK, Notley LM, Wunsch RM, et al. Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4′-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos 2002; 30: 869–74