Abstract
Cytochrome P450 (CYP) 2D6 is one of the most investigated CYPs in relation to genetic polymorphism, but accounts for only a small percentage of all hepatic CYPs (∼2–4%). There is a large interindividual variation in the enzyme activity of CYP2D6. The enzyme is largely non-inducible and metabolizes ∼25% of current drugs. Typical substrates for CYP2D6 are largely lipophilic bases and include some antidepressants, antipsychotics, antiarrhythmics, antiemetics, β-adrenoceptor antagonists (β-blockers) and opioids. The CYP2D6 activity ranges considerably within a population and includes ultrarapid metabolizers (UMs), extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs). There is a considerable variability in the CYP2D6 allele distribution among different ethnic groups, resulting in variable percentages of PMs, IMs, EMs and UMs in a given population.
To date, 74 allelic variants and a series of subvariants of the CYP2D6 gene have been reported and the number of alleles is still growing. Among these are fully functional alleles, alleles with reduced function and null (non-functional) alleles, which convey a wide range of enzyme activity, from no activity to ultrarapid metabolism of substrates. As a consequence, drug adverse effects or lack of drug effect may occur if standard doses are applied. The alleles *10, *17, *36 and *41 give rise to substrate-dependent decreased activity. Null alleles of CYP2D6 do not encode a functional protein and there is no detectable residual enzymatic activity. It is clear that alleles *3, *4, *5, *6, *7, *8, *11, *12, *13, *14, *15, *16, *18, *19, *20, *21, *38, *40, *42, *44, *56 and *62 have no enzyme activity. They are responsible for the PM phenotype when present in homozygous or compound heterozygous constellations. These alleles are of clinical significance as they often cause altered drug clearance and drug response. Among the most important variants are CYP2D6*2, *3, *4, *5, *10, *17 and *41. On the other hand, the CYP2D6 gene is subject to copy number variations that are often associated with the UM phenotype. Marked decreases in drug concentrations have been observed in UMs with tramadol, venlafaxine, morphine, mirtazapine and metoprolol. The functional impact of CYP2D6 alleles may be substrate-dependent. For example, CYP2D6*17 is generally considered as an allele with reduced function, but it displays remarkable variability in its activity towards substrates such as dextromethorphan, risperidone, codeine and haloperidol.
The clinical consequence of the CYP2D6 polymorphism can be either occurrence of adverse drug reactions or altered drug response. Drugs that are most affected by CYP2D6 polymorphisms are commonly those in which CYP2D6 represents a substantial metabolic pathway either in the activation to form active metabolites or clearance of the agent. For example, encainide metabolites are more potent than the parent drug and thus QRS prolongation is more apparent in EMs than in PMs. In contrast, propafenone is a more potent b-blocker than its metabolites and the β-blocking activity during propafenone therapy is more prominent in PMs than EMs, as the parent drug accumulates in PMs. Since flecainide is mainly eliminated through renal excretion, and both R- and S-flecainide possess equivalent potency for sodium channel inhibition, the CYP2D6 phenotype has a minor impact on the response to flecainide. Since the contribution of CYP2D6 is greater for metoprolol than for carvedilol, propranolol and timolol, a stronger gene-dose effect is seen with this β-blocker, while such an effect is lesser or marginal in other β-blockers.
Concordant genotype-phenotype correlation provides a basis for predicting the phenotype based on genetic testing, which has the potential to achieve optimal pharmacotherapy. However, 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 of subjects.
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References
Nebert DW, Russell DW. Clinical importance of the cytochromes P450. Lancet 2002; 360: 1155–62
Nelson D. Cytochrome P450 homepage [online]. Available from URL: http://drnelson.utmem.edu/CytochromeP450.html [Accessed 2009 Sep 1]
Rendic S. Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev 2002; 34: 83–448
Ingelman-Sundberg M, Sim SC, Gomez A, et al. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 2007; 116: 496–526
Kirchheiner J, Seeringer A. Clinical implications of pharmacogenetics of cytochrome P450 drug metabolizing enzymes. Biochim Biophys Acta 2007; 1770: 489–94
Tomalik-Scharte D, Lazar A, Fuhr U, et al. The clinical role of genetic polymorphisms in drug-metabolizing enzymes. Pharmacogenomics J 2008; 8:4–15
Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev 2009; 41: 89–295
Human Cytochrome P450 (CYP) Allele Nomenclature Committee [online]. Available from URL: http://www.cypalleles.ki.se/ [Accessed 2009 Sep1]
Alexanderson B, Evans DA, Sjoqvist F. Steady-state plasma levels of nortriptyline in twins: influence of genetic factors and drug therapy. Br Med J 1969; 4: 764–8
Mahgoub A, Idle JR, Dring LG, et al. Polymorphic hydroxylation of debrisoquine in man. Lancet 1977; II: 584–6
Eichelbaum M, Spannbrucker N, Steincke B, et al. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol 1979; 16: 183–7
Cascorbi I. Pharmacogenetics of cytochrome P4502D6: genetic background and clinical implication. Eur J Clin Invest 2003; 33: 17–22
Gardiner SJ, Begg EJ. Pharmacogenetics drug-metabolizing enzymes, and clinical practice. Pharmacol Rev 2006; 58: 521–90
Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 2005; 5: 6–13
Zhou SF, Di YM, Chan E, et al. Clinical pharmacogenetics and potential application in personalized medicine. Curr Drug Metab 2008; 9: 738–84
Marechal JD, Kemp CA, Roberts GC, et al. Insights into drug metabolism by cytochromes P450 from modelling studies of CYP2D6-drug interactions. Br J Pharmacol 2008; 153 Suppl. 1: S82–9
Bock KW, Schrenk D, Forster A, et al. The influence of environmental and genetic factors on CYP2D6, CYP1A2 and UDP-glucuronosyltransferases in man using sparteine, caffeine, and paracetamol as probes. Pharmacogenetics 1994;4:209–18
Zanger UM, Raimundo S, Eichelbaum M. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol 2004; 369: 23–37
Sachse C, Brockmoller J, Bauer S, et al. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 1997; 60: 284–95
Bradford LD. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 2002; 3: 229–43
Wang SL, Huang JD, Lai MD, et al. Molecular basis of genetic variation in debrisoquin hydroxylation in Chinese subjects: polymorphism in RFLP and DNA sequence of CYP2D6. Clin Pharmacol Ther 1993; 53: 410–8
Johansson I, Yue QY, Dahl ML, et al. Genetic analysis of the interethnic difference between Chinese and Caucasians in the polymorphic metabolism of debrisoquine and codeine. EurJ Clin Pharmacol 1991; 40: 553–6
Dahl ML, Johansson I, Bertilsson L, et al. Ultrarapid hydroxylation of debrisoquine in a Swedish population: analysis of the molecular genetic basis. J Pharmacol Exp Ther 1995; 274: 516–20
Aklillu E, Persson I, Bertilsson L, et al. Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther 1996; 278: 441–6
Gough AC, Smith CA, Howell SM, et al. Localization of the CYP2D gene locus to human chromosome 22q13.1 by polymerase chain reaction, in situ hybridization, and linkage analysis. Genomics 1993; 15: 430–2
Kimura S, Umeno M, Skoda RC, et al. The human debrisoquine 4-hydroxy- lase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene. Am J Hum Genet 1989; 45: 889–904
Eichelbaum M, Baur MP, Dengler HJ, et al. Chromosomal assignment of human cytochrome P-450 (debrisoquine/sparteine type) to chromosome 22. Br J Clin Pharmacol 1987; 23: 455–8
Heim M, Meyer UA. Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification. Lancet 1990; 336: 529–32
Heim MH, Meyer UA. Evolution of a highly polymorphic human cytochrome P450 gene cluster: CYP2D6. Genomics 1992; 14: 49–58
Steen VM, Andreassen OA, Daly AK, et al. Detection of the poor metabolizer-associated CYP2D6 (D) gene deletion allele by long-PCR technology. Pharmacogenetics 1995; 5: 215–2331.
Pai HV, Kommaddi RP, Chinta SJ, et al. A frameshiftmutation and alternate splicing in human brain generate a functional form of the pseudogene cytochrome P4502D7 that demethylates codeine to morphine. J Biol Chem 2004; 279: 27383–9
Gaedigk A, Gaedigk R, Leeder JS. CYP2D7 splice variants in human liver and brain: does CYP2D7 encode functional protein? Biochem Biophys Res Commun 2005; 336: 1241–50
Zhang WY, Tu YB, Haining RL, et al. Expression and functional analysis of CYP2D6.24, CYP2D6.26, CYP2D6.27, and CYP2D7 isozymes. Drug Metab Dispos 2009; 37: 1–4
Nelson DR, Zeldin DC, Hoffman SM, et al. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics 2004; 14: 1–18
Eichelbaum M, Spannbrucker N, Dengler HJ. Proceedings: N-oxidation of sparteine in man and its interindividual differences. Naunyn Schmiedebergs Arch Pharmacol 1975; 287 Suppl.: R94
Osikowska-Evers B, Dayer P, Meyer UA, et al. Evidence for altered catalytic properties of the cytochrome P-450 involved in sparteine oxidation in poor metabolizers. Clin Pharmacol Ther 1987; 41: 320–5
Eichelbaum M, Spannbrucker N, Dengler HJ. Influence of the defective metabolism of sparteine on its pharmacokinetics. Eur J Clin Pharmacol 1979; 16: 189–94
Eichelbaum M, Mineshita S, Ohnhaus EE, et al. The influence of enzyme induction on polymorphic sparteine oxidation. Br J Clin Pharmacol 1986; 22: 49–53
Eichelbaum M, Reetz KP, Schmidt EK, et al. The genetic polymorphism of sparteinemetabolism. Xenobiotica 1986; 16: 465–81
Ebner T, Meese CO, Eichelbaum M. Mechanism of cytochrome P450 2D6-catalyzed sparteine metabolism in humans. Mol Pharmacol 1995; 48: 1078–86
Tyndale RF, Gonzalez FJ, Hardwick JP, et al. Sparteine metabolism capacity in human liver: structural variants of human P450IID6 as assessed by immunochemistry. Pharmacol Toxicol 1990; 67: 14–8
Schellens JH, van der Wart JH, Brugman M, et al. Influence of enzyme induction and inhibition on the oxidation of nifedipine, sparteine, mephenytoin and antipyrine in humans as assessed by a “cocktail” study design. J Pharmacol Exp Ther 1989; 249: 638–45
Madan A, Graham RA, Carroll KM, et al. Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. Drug Metab Dispos 2003; 31: 421–31
Zanger UM, Klein K, Saussele T, et al. Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. Pharmacogenomics 2007; 8: 743–59
Woolhouse NM, Andoh B, Mahgoub A, et al. Debrisoquin hydroxylation polymorphism among Ghanaians and Caucasians. Clin Pharmacol Ther 1979; 26: 584–91
Eiermann B, Edlund PO, Tjernberg A, et al. 1- and 3-hydroxylations, in addition to 4-hydroxylation, of debrisoquine are catalyzed by cytochrome P450 2D6 in humans. Drug Metab Dispos 1998; 26: 1096–101
Gonzalez FJ, Skoda RC, Kimura S, et al. Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 1988; 331: 442–6
Evans DA, Mahgoub A, Sloan TP, et al. A family and population study of the genetic polymorphism of debrisoquine oxidation in a White British population. J Med Genet 1980; 17: 102–5
Alvan G, Bechtel P, Iselius L, et al. Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol 1990; 39: 533–7
Bertilsson L, Lou YQ, Du YL, et al. Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clin Pharmacol Ther 1992; 51: 388–97
Dayer P, Leemann T, Striberni R. Dextromethorphan O-demethylation in liver microsomes as a prototype reaction to monitor cytochrome P-450 db1 activity. Clin Pharmacol Ther 1989; 45: 34–40
Jacqz-Aigrain E, Funck-Brentano C, Cresteil T. CYP2D6- and CYP3A-dependent metabolism of dextromethorphan in humans. Pharmacogenetics 1993; 3: 197–204
Schmid B, Bircher J, Preisig R, et al. Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation. Clin Pharmacol Ther 1985; 38: 618–24
Kohler D, Hartter S, Fuchs K, et al. CYP2D6 genotype and phenotyping by determination of dextromethorphan and metabolites in serum of healthy controls and of patients under psychotropic medication. Pharmacogenetics 1997; 7: 453–61
Hiroi T, Chow T, Imaoka S, et al. Catalytic specificity ofCYP2D isoforms in rat and human. Drug Metab Dispos 2002; 30: 970–6
Carcillo JA, Adedoyin A, Burckart GJ, et al. Coordinated intrahepatic and extrahepatic regulation of cytochrome P4502D6 in healthy subjects and in patients after liver transplantation. Clin Pharmacol Ther 2003; 73: 456–67
Mankowski DC. The role of CYP2C19 in the metabolism of (±) bufuralol, the prototypic substrate of CYP2D6. Drug Metab Dispos 1999; 27: 1024–8
Yamazaki H, Guo Z, Persmark M, et al. Bufuralol hydroxylation by cytochrome P450 2D6 and 1A2 enzymes in human liver microsomes. Mol Pharmacol 1994; 46: 568–77
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
Subrahmanyam V, Renwick AB, Walters DG, et al. Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human livermicrosomes. Drug Metab Dispos 2001; 29: 1146–55
Paar WD, Frankus P, Dengler HJ. The metabolism of tramadol by human livermicrosomes. Clin Investig 1992; 70: 708–10
Wu WN, McKown LA, Liao S. Metabolism of the analgesic drug Ultram® (tramadol hydrochloride) in humans: API-MS and MS/MS characterization of metabolites. Xenobiotica 2002; 32: 411–25
Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet 2004; 43: 879–923
Yuan R, Madani S, Wei XX, et al. Evaluation of cytochrome P450 probe substrates commonly used by the pharmaceutical industry to study in vitro drug interactions. Drug Metab Dispos 2002; 30: 1311–9
Zhou SF, Liu JP, Lai XS. Substrate specificity, inhibitors and regulation of human cytochrome P450 2D6 and implications in drug development. Curr Med Chem 2009; 16: 2661–805
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
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
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
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
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
Venkatakrishnan K, Greenblatt DJ, von Moltke LL, et al. Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4. J Clin Pharmacol 1998; 38: 112–21
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
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
Breyer-Pfaff U, Fischer D, Winne D. Biphasic kinetics of quaternary ammonium glucuronide formation from amitriptyline and diphenhydramine in human livermicrosomes. Drug Metab Dispos 1997; 25: 340–5
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
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
von Moltke LL, Greenblatt DJ, Duan SX, et al. Human cytochromes mediating N-demethylation of fluoxetine in vitro. Psychopharmacology (Berl) 1997; 132: 402–7
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
Bloomer JC, Woods FR, Haddock RE, et al. The role of cytochrome P4502D6 in the metabolism of paroxetine by human liver microsomes. Br J ClinPharmacol 1992; 33: 521–3
Obach RS, Cox LM, Tremaine LM. Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study. Drug Metab Dispos 2005; 33: 262–70
Xu ZH, Wang W, Zhao XJ, et al. Evidence for involvement of polymorphic CYP2C19 and 2C9 in the N-demethylation of sertraline in human liver microsomes. Br J Clin Pharmacol 1999; 48: 416–23
Kobayashi K, Ishizuka T, Shimada N, et al. Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro. Drug Metab Dispos 1999; 27: 763–6
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
Brachtendorf L, Jetter A, Beckurts KT, et al. Cytochrome P450 enzymes contributing to demethylation of maprotiline in man. Pharmacol Toxicol 2002; 90: 144–9
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
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
Otton SV, Ball SE, Cheung SW, et al. Venlafaxine oxidation in vitro is catalysed by CYP2D6. BrJClin Pharmacol 1996; 41: 149–56
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
Yoshii K, Kobayashi K, Tsumuji M, et al. Identification of human cytochrome P450 isoforms involved in the 7-hydroxylation of chlorpromazine by human livermicrosomes. Life Sci 2000; 67: 175–84
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
Shiraga T, Kaneko H, Iwasaki K, et al. Identification of cytochrome P450 enzymes involved in the metabolism of zotepine, an antipsychotic drug, in human liver microsomes. Xenobiotica 1999; 29: 217–29
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
Jerling M, Dahl ML, Aberg-Wistedt A, et al. The CYP2D6 genotype predicts the oral clearance of the neuroleptic agents perphenazine and zuclo-penthixol. Clin Pharmacol Ther 1996; 59: 423–8
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
Tateishi T, Watanabe M, Kumai T, et al. CYP3A is responsible for N-deal-kylation of haloperidol and bromperidol and oxidation of their reduced forms by human livermicrosomes. Life Sci 2000; 67: 2913–20
Kudo S, Odomi M. Involvement of human cytochrome P450 3A4 in reduced haloperidol oxidation. Eur J Clin Pharmacol 1998; 54: 253–9
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
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
Sanwald P, David M, Dow J. Use of electrospray ionization liquid chromatography-mass spectrometry to study the role of CYP2D6 in the in vitro metabolism of 5-hydroxytryptamine receptor antagonists. J Chromatogr B Biomed Appl 1996; 678: 53–61
Firkusny L, Kroemer HK, Eichelbaum M. In vitro characterization of cytochrome P450 catalysed metabolism of the antiemetic tropisetron. Biochem Pharmacol 1995; 49: 1777–84
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
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
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
Kobayashi K, Chiba K, Yagi T, et al. Identification of cytochrome P450 isoforms involved in citalopram N-demethylation by human liver microsomes. J Pharmacol Exp Ther 1997; 280: 927–33
Rochat B, Amey M, Gillet M, et al. Identification of three cytochrome P450 isozymes involved in N-demethylation of citalopram enantiomers in human livermicrosomes. Pharmacogenetics 1997; 7: 1–10
Olesen OV, Linnet K. Studies on the stereoselectivemetabolism of citalopram by human liver microsomes and cDNA-expressed cytochrome P450 enzymes. Pharmacology 1999; 59: 298–309
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
von Moltke LL, Greenblatt DJ, Grassi JM, et al. Gepirone and 1-(2- pyrimidinyl)-piperazine in vitro: human cytochromes mediating transformation and cytochrome inhibitory effects. Psychopharmacology (Berl) 1998; 140: 293–9
Greenblatt DJ, Von Moltke LL, Giancarlo GM, et al. Human cytochromes mediating gepirone biotransformation at low substrate concentrations. Biopharm Drug Dispos 2003; 24: 87–94
Skinner MH, Kuan HY, Pan A, et al. Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers. Clin Pharmacol Ther 2003; 73: 170–7
Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev 2001; 7: 249–64
Wang JS, DeVane CL. Involvement ofCYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro. Drug Metab Dispos 2003; 31: 742–7
Bottiger Y, Dostert P, Benedetti MS, et al. Involvement ofCYP2D6 but not CYP2C19 in nicergoline metabolism in humans. Br J Clin Pharmacol 1996; 42:707–11
Grace JM, Kinter MT, Macdonald TL. Atypical metabolism of deprenyl and its enantiomer, (S)-(+)- N, α-dimethyl- N-propynylphenethylamine, by cytochrome P450 2D6. Chem Res Toxicol 1994; 7: 286–90
Hidestrand M, Oscarson M, Salonen JS, et al. CYP2B6 and CYP2C19 as the major enzymes responsible for the metabolism of selegiline, a drug used in the treatment of Parkinson’s disease, as revealed from experiments with recombinant enzymes. Drug Metab Dispos 2001; 29: 1480–4
Gras J, Llenas J, Jansat JM, et al. Almotriptan, a new anti-migraine agent: a review. CNS Drug Rev 2002; 8: 217–34
Pascual J. Almotriptan: an effective and well-tolerated treatment for migraine pain. Drugs Today (Barc) 2003; 39 Suppl. D: 31–6
Keam SJ, Goa KL, Figgitt DP. Almotriptan: a review of its use in migraine. Drugs 2002; 62: 387–414
McEnroe JD, Fleishaker JC. Clinical pharmacokinetics of almotriptan, a serotonin 5-HT1B/1D receptor agonist for the treatment of migraine. Clin Pharmacokinet 2005; 44: 237–46
Pichard L, Gillet G, Bonfils C, et al. Oxidative metabolism of zolpidem by human liver cytochrome P450s. Drug Metab Dispos 1995; 23: 1253–62
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
Barner EL, Gray SL. Donepezil use in Alzheimer disease. Ann Pharmacother 1998; 32: 70–7
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
Jann MW, Shirley KL, Small GW. Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors. Clin Pharmacokinet 2002; 41: 719–39
Obach RS, Pablo J, Mash DC. Cytochrome P4502D6 catalyzes the O-demethylation of the psychoactive alkaloid ibogaine to 12-hydroxy-ibogamine. Drug Metab Dispos 1998; 26: 764–8
Davies BJ, Coller JK, Somogyi AA, et al. CYP2B6, CYP2D6, and CYP3A4 catalyze the primary oxidative metabolism of perhexiline enantiomers by human liver microsomes. Drug Metab Dispos 2007; 35: 128–38
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
Beverage JN, Sissung TM, Sion AM, et al. CYP2D6 polymorphisms and the impact on tamoxifen therapy. J Pharm Sci 2007; 96: 2224–31
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
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
Dehal SS, Kupfer D. CYP2D6 catalyzes tamoxifen 4-hydroxylation in human liver. Cancer Res 1997; 57: 3402–6
Narimatsu S, Kariya S, Isozaki S, et al. Involvement ofCYP2D6 in oxidative metabolism of cinnarizine and flunarizine in human liver microsomes. Biochem Biophys Res Commun 1993; 193: 1262–8
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. BiochemPharmacol 1996; 51: 165–72
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
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 livermicrosomes. Pharmacogenetics 1996; 6: 449–57
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
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
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
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
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
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
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
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
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
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
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
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
Kudo S, Okumura H, Miyamoto G, et al. Cytochrome P-450 isoforms involved in carboxylic acid ester cleavage of Hantzsch pyridine ester of pranidipine. Drug Metab Dispos 1999; 27: 303–8
Kumar GN, Rodrigues AD, Buko AM, et al. Cytochrome P450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J Pharmacol Exp Ther 1996; 277: 423–31
Erickson DA, Mather G, Trager WF, et al. Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450. Drug Metab Dispos 1999; 27: 1488–95
Voorman RL, Maio SM, Hauer MJ, et al. Metabolism of delavirdine, a human immunodeficiency virus type-1 reverse transcriptase inhibitor, by microsomal cytochrome P450 in humans, rats, and other species: probable involvement of CYP2D6 and CYP3A. Drug Metab Dispos 1998; 26: 631–9
Halliday RC, Jones BC, Smith DA, et al. An investigation of the interaction between halofantrine, CYP2D6 and CYP3A4: studies with human liver microsomes and heterologous enzyme expression systems. Br J Clin Pharmacol 1995; 40: 369–78
Gibbs JP, Hyland R, Youdim K. Minimizing polymorphic metabolism in drug discovery: evaluation of the utility of in vitro methods for predicting pharmacokinetic consequences associated with CYP2D6 metabolism. Drug Metab Dispos 2006; 34: 1516–22
Evans WE, Relling MV, Petros WP, et al. Dextromethorphan and caffeine as probes for simultaneous determination of debrisoquin-oxidation and N-acetylation phenotypes in children. Clin Pharmacol Ther 1989; 45: 568–73
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
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
Zoble RG, Kirsten EB, Brewington J. Pharmacokinetic and pharmacodynamic evaluation of propafenone in patients with ventricular arrhythmia. Propafenone Research Group. Clin Pharmacol Ther 1989; 45: 535–41
Gram LF, Christiansen J. First-pass metabolism of imipramine in man. Clin Pharmacol Ther 1975; 17: 555–63
Holliday SM, Benfield P. Venlafaxine: a review of its pharmacology and therapeutic potential in depression. Drugs 1995; 49: 280–94
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
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
Ebner T, Eichelbaum M. The metabolism of aprindine in relation to the sparteine/debrisoquinepolymorphism. BrJClinPharmacol 1993; 35:426–30
Wang LL, Li Y, Zhou SF. A bioinformatics approach for the phenotype prediction of nonsynonymous single nucleotide polymorphisms in human cytochromes P450. Drug Metab Dispos 2009; 37: 977–91
Kagimoto M, Heim M, Kagimoto K, et al. Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine: study of the functional significance of individual mutations by expression of chimeric genes. J Biol Chem 1990; 265: 17209–14
Evert B, Eichelbaum M, Haubruck H, et al. Functional properties of CYP2D6.1 (wild-type) and CYP2D6.7 (His324Pro) expressed by recombinant baculovirus in insect cells. Naunyn Schmiedebergs Arch Pharmacol 1997; 355: 309–18
Gaedigk A, Blum M, Gaedigk R, et al. Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism. Am J Hum Genet 1991; 48: 943–50
Skoda RC, Gonzalez FJ, Demierre A, et al. Two mutant alleles of the human cytochrome P-450db 1 gene (P450C2D 1) associated with genetically deficient metabolism of debrisoquine and other drugs. Proc Natl Acad Sci U S A 1988; 85: 5240–3
Marez D, Legrand M, Sabbagh N, et al. Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of48 mutations and 53 alleles, their frequencies and evolution. Pharmacogenetics 1997; 7: 193–202
Dahl ML, Johansson I, Palmertz MP, et al. Analysis of the CYP2D6 gene in relation to debrisoquin and desipramine hydroxylation in a Swedish population. Clin Pharmacol Ther 1992; 51: 12–7
Masimirembwa C, Hasler J, Bertilssons L, et al. Phenotype and genotype analysis of debrisoquine hydroxylase (CYP2D6) in a Black Zimbabwean population: reduced enzyme activity and evaluation of metabolic correlation ofCYP2D6 probe drugs. EurJClin Pharmacol 1996; 51: 117–22
Simooya OO, Njunju E, Hodjegan AR, et al. Debrisoquine and metoprolol oxidation in Zambians: a population study. Pharmacogenetics 1993; 3:205–8
Gaedigk A, Bradford LD, Alander SW, et al. CYP2D6*36 gene arrangements within the CYP2D6 locus: association of CYP2D6*36 with poor metabolizer status. Drug Metab Dispos 2006; 34: 563–9
Evert B, Griese EU, Eichelbaum M. A missense mutation in exon 6 of the CYP2D6 gene leading to a histidine 324 to proline exchange is associated with the poor metabolizer phenotype of sparteine. Naunyn Schmiedebergs Arch Pharmacol 1994; 350: 434–9
Marez D, Sabbagh N, Legrand M, et al. A novel CYP2D6 allele with an abolished splice recognition site associated with the poor metabolizer phenotype. Pharmacogenetics 1995; 5: 305–11
Marez-Allorge D, Ellis SW, Lo Guidice JM, et al. A rare G2061 insertion affecting the open reading frame of CYP2D6 and responsible for the poor metabolizer phenotype. Pharmacogenetics 1999; 9: 393–6
Li L, Pan RM, Porter TD, et al. New cytochrome P450 2D6*56 allele identified by genotype/phenotype analysis of cryopreserved human hepatocytes. Drug Metab Dispos 2006; 34: 1411–6
Klein K, Tatzel S, Raimundo S, et al. A natural variant of the heme-binding signature (R441C) resulting in complete loss of function ofCYP2D6. Drug Metab Dispos 2007; 35: 1247–50
Marez D, Legrand M, Sabbagh N, et al. An additional allelic variant of the CYP2D6 genecausing impaired metabolism of sparteine. Hum Genet 1996; 97: 668–70
Wang SL, Lai MD, Huang JD. G169R mutation diminishes the metabolic activity of CYP2D6 in Chinese. Drug Metab Dispos 1999; 27: 385–8
Kubota T, Yamaura Y, Ohkawa N, et al. Frequencies of CYP2D6 mutant alleles in a normal Japanese population and metabolic activity of dextromethorphan O-demethylation in different CYP2D6 genotypes. Br J Clin Pharmacol 2000; 50: 31–4
Daly AK, Brockmoller J, Broly F, et al. Nomenclature for human CYP2D6 alleles. Pharmacogenetics 1996; 6: 193–201
Sakuyama K, Sasaki T, Ujiie S, et al. Functional characterization of 17 CYP2D6 allelic variants (CYP2D6.2, 10, 14A-B, 18, 27, 36, 39, 47-51,53-55, and 57). Drug Metab Dispos 2008; 36: 2460–7
Ji L, Pan S, Marti-Jaun J, et al. Single-step assays to analyze CYP2D6 gene polymorphisms in Asians: allele frequencies and a novel *14B allele in mainland Chinese. Clin Chem 2002; 48: 983–8
Yokoi T, Kosaka Y, Chida M, et al. A new CYP2D6 allele with a nine base insertion in exon 9 in a Japanese population associated with poor metabolizer phenotype. Pharmacogenetics 1996; 6: 395–401
Steen VM, Molven A, Aarskog NK, et al. Homologous unequal cross-over involving a 2.8 kb direct repeat as a mechanism for the generation of allelic variants of human cytochrome P450 CYP2D6 gene. Hum Mol Genet 1995; 4: 2251–7
Idle JR, Corchero J, Gonzalez FJ. Medical implications ofHGP’s sequence of chromosome 22. Lancet 2000; 355: 319
Panserat S, Mura C, Gerard N, et al. An unequal cross-over event within the CYP2D gene cluster generates a chimeric CYP2D7/CYP2D6 gene which is associated with the poor metabolizer phenotype. Br J Clin Pharmacol 1995; 40: 361–7
Daly AK, Fairbrother KS, Andreassen OA, et al. Characterization and PCR-based detection of two different hybrid CYP2D7P/CYP2D6 alleles associated with the poor metabolizer phenotype. Pharmacogenetics 1996; 6: 319–28
Johansson I, Oscarson M, Yue QY, et al. Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 1994; 46: 452–9
Ishiguro A, Kubota T, Sasaki H, et al. A long PCR assay to distinguish CYP2D6*5 and a novel CYP2D6 mutant allele associated with an 11-kb EcoRI haplotype. Clin Chim Acta 2004; 347: 217–21
Leathart JB, London SJ, Steward A, et al. CYP2D6 phenotype-genotype relationships in African-Americans and Caucasians in Los Angeles. Pharmacogenetics 1998; 8: 529–41
Yokota H, Tamura S, Furuya H, et al. Evidence for a new variant CYP2D6 allele CYP2D6J in a Japanese population associated with lower in vivo rates of sparteinemetabolism. Pharmacogenetics 1993; 3: 256–63
Huang J, Chuang SK, Cheng CL, et al. Pharmacokinetics of metoprolol enantiomers in Chinese subjects of major CYP2D6 genotypes. Clin Pharmacol Ther 1999; 65: 402–7
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
Yamazaki S, Sato K, Suhara K, et al. Importance of the proline-rich region following signal-anchor sequence in the formation of correct conformation of microsomal cytochrome P-450s. J Biochem 1993; 114: 652–7
Shen H, He MM, Liu H, et al. Comparative metabolic capabilities and in hibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17. Drug Metab Dispos 2007; 35: 1292–300
Garcia-Barcelo M, Chow LY, Lam KL, et al. Occurrence of CYP2D6 gene duplication in Hong Kong Chinese. Clin Chem 2000; 46: 1411–3
Mitsunaga Y, Kubota T, Ishiguro A, et al. Frequent occurrence of CYP2D6*10 duplication allele in a Japanese population. Mutat Res 2002; 505: 83–5
Masimirembwa C, Persson I, Bertilsson L, et al. A novel mutant variant of the CYP2D6 gene (CYP2D6*17) common in a Black African population: association with diminished debrisoquine hydroxylase activity. Br J Clin Pharmacol 1996;42:713–9
Wennerholm A, Johansson I, Massele AY, et al. Decreased capacity for debrisoquine metabolism among Black Tanzanians: analyses of the CYP2D6 genotype and phenotype. Pharmacogenetics 1999; 9: 707–14
Griese EU, Asante-Poku S, Ofori-Adjei D, et al. Analysis of the CYP2D6 gene mutations and their consequences for enzyme function in a West African population. Pharmacogenetics 1999; 9: 715–23
Oscarson M, Hidestrand M, Johansson I, et al. A combination of mutations in the CYP2D6*17 (CYP2D6Z) allele causes alterations in enzyme function. Mol Pharmacol 1997; 52: 1034–40
Bogni A, Monshouwer M, Moscone A, et al. Substrate specific metabolism by polymorphic cytochrome P450 2D6 alleles. Toxicol In Vitro 2005; 19: 621–9
Cai WM, Nikoloff DM, Pan RM, et al. CYP2D6 genetic variation in healthy adults and psychiatric African-American subjects: implications for clinical practice and genetic testing. Pharmacogenomics J 2006; 6: 343–50
Fukuda T, Nishida Y, Imaoka S, et al. The decreased in vivo clearance of CYP2D6 substrates by CYP2D6*10 might be caused not only by the lowexpression but also by low affinity ofCYP2D6. Arch Biochem Biophys 2000; 380: 303–8
Chida M, Ariyoshi N, Yokoi T, et al. New allelic arrangement CYP2D6*36 × 2 found in a Japanese poor metabolizer of debrisoquine. Pharmacogenetics 2002; 12: 659–62
Raimundo S, Fischer J, Eichelbaum M, et al. Elucidation of the genetic basis of the common ‘intermediate metabolizer’ phenotype for drug oxidation by CYP2D6. Pharmacogenetics 2000; 10: 577–81
Raimundo S, Toscano C, Klein K, et al. A novel intronic mutation, 2988G>A, with high predictivity for impaired function of cytochrome P450 2D6 in White subjects. Clin Pharmacol Ther 2004; 76: 128–38
Toscano C, Klein K, Blievernicht J, et al. Impaired expression of CYP2D6 in intermediate metabolizers carrying the *41 allele caused by the intronic SNP 2988G>A: evidence for modulation of splicing events. Pharmacogenet Genomics 2006; 16: 755–66
Rau T, Diepenbruck S, Diepenbruck I, et al. The 2988G>A polymorphism affects splicing of a CYP2D6 minigene. Clin Pharmacol Ther 2006; 80: 555–58; author reply 558-60
Soyama A, Kubo T, Miyajima A, et al. Novel nonsynonymous single nucleotide polymorphisms in the CYP2D6 gene. Drug Metab Pharmacokinet 2004; 19: 313–9
Rowland P, Blaney FE, Smyth MG, et al. Crystal structure of human cytochrome P450 2D6. J Biol Chem 2006; 281: 7614–22
Soyama A, Saito Y, Kubo T, et al. Sequence-based analysis of the CYP2D6*36-CYP2D6*10 tandem-type arrangement, a major CYP2D6*10 haplotype in the Japanese population. Drug Metab Pharmacokinet 2006; 21: 208–16
Gaedigk A, Bhathena A, Ndjountche L, et al. Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans. Pharmacogenomics J 2005; 5: 173–82
Gaedigk A, Ndjountche L, Leeder JS, et al. Limited association of the 2988G>A single nucleotide polymorphism with CYP2D6*41 in Black subjects. Clin Pharmacol Ther 2005; 77: 228–30; author reply 230-1
Johansson I, Lundqvist E, Bertilsson L, et al. Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc Natl Acad Sci U S A 1993; 90: 11825–9
Flanagan JU, Marechal JD, Ward R, et al. Phe120 contributes to the regiospecificity of cytochrome P450 2D6: mutation leads to the formation of a novel dextromethorphan metabolite. Biochem J 2004; 380: 353–60
Keizers PH, Lussenburg BM, de Graaf C, et al. Influence of phenylalanine 120 on cytochrome P450 2D6 catalytic selectivity and regiospecificity: crucial role in 7-methoxy-4-(aminomethyl)-coumarin metabolism. Biochem Pharmacol 2004; 68: 2263–71
McLaughlin LA, Paine MJ, Kemp CA, et al. Why is quinidine an inhibitor of cytochrome P450 2D6? The role of key active-site residues in quinidine binding. J Biol Chem 2005; 280: 38617–24
Solus JF, Arietta BJ, Harris JR, et al. Genetic variation in eleven phase I drug metabolism genes in an ethnically diverse population. Pharmacogenomics 2004; 5: 895–931
Panserat S, Mura C, Gerard N, et al. DNA haplotype-dependent differences in the amino acid sequence of debrisoquine 4-hydroxylase (CYP2D6): evidence for two major allozymes in extensive metabolisers. Hum Genet 1994; 94: 401–6
Gaedigk A, Ndjountche L, Divakaran K, et al. Cytochrome P4502D6 (CYP2D6) gene locus heterogeneity: characterization of gene duplication events. Clin Pharmacol Ther 2007; 81: 242–51
Bertilsson L, Dahl ML, Sjoqvist F, et al. Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet 1993; 341:63
Aklillu E, Herrlin K, Gustafsson LL, et al. Evidence for environmental influence on CYP2D6-catalysed debrisoquine hydroxylation as demonstrated by phenotyping and genotyping of Ethiopians living in Ethiopia or in Sweden. Pharmacogenetics 2002; 12: 375–83
Nishida Y, Fukuda T, Yamamoto I, et al. CYP2D6 genotypes in a Japanese population: low frequencies of CYP2D6 gene duplication but high frequency of CYP2D6*10. Pharmacogenetics 2000; 10: 567–70
Bathum L, Johansson I, Ingelman-Sundberg M, et al. Ultrarapid metabolism of sparteine: frequency of alleles with duplicated CYP2D6 genes in a Danish population as determined by restriction fragment length polymorphism and long polymerase chain reaction. Pharmacogenetics 1998; 8: 119–23
Bathum L, Skjelbo E, Mutabingwa TK, et al. Phenotypes and genotypes for CYP2D6 and CYP2C19 in a Black Tanzanian population. Br J Clin Pharmacol 1999; 48: 395–401
Sistonen J, Fuselli S, Palo JU, et al. Pharmacogenetic variation at CYP2C9, CYP2C19, and CYP2D6 at global and microgeographic scales. Pharmacogenet Genomics 2009; 19: 170–9
Sistonen J, Sajantila A, Lao O, et al. CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure. Pharmacogenet Genomics 2007; 17: 93–101
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
Stamer UM, Musshoff F, Kobilay M, et al. Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin Pharmacol Ther 2007; 82: 41–7
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
Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J 2007; 7: 257–65
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
Kirchheiner J, Heesch C, Bauer S, et al. Impact of the ultrarapid metabolizer genotype of cytochrome P450 2D6 on metoprolol pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 2004; 76: 302–12
Goryachkina K, Burbello A, Boldueva S, et al. CYP2D6 is a major determinant of metoprolol disposition and effects in hospitalized Russian patients treated for acute myocardial infarction. Eur J Clin Pharmacol 2008; 64: 1163–73
Dalen P, Frengell C, Dahl ML, et al. Quick onset of severe abdominal pain aftercodeine in an ultrarapid metabolizer of debrisoquine. Ther Drug Monit 1997; 19: 543–4
Horai Y, Nakano M, Ishizaki T, et al. Metoprolol and mephenytoin oxidation polymorphisms in Far Eastern Oriental subjects: Japanese versus mainland Chinese. Clin Pharmacol Ther 1989; 46: 198–207
Sohn DR, Shin SG, Park CW, et al. Metoprolol oxidation polymorphism in a Korean population: comparison with native Japanese and Chinese populations. Br J Clin Pharmacol 1991; 32: 504–7
Horai Y, Taga J, Ishizaki T, et al. Correlations among the metabolic ratios of three test probes (metoprolol, debrisoquine and sparteine) for genetically determined oxidation polymorphism in a Japanese population. Br J Clin Pharmacol 1990;29: 111–5
Lamba V, Lamba JK, Dilawari JB, et al. Genetic polymorphism of CYP2D6 in North Indian subjects. Eur J Clin Pharmacol 1998; 54: 787–91
Gaedigk A, Bradford LD, Marcucci KA, et al. Unique CYP2D6 activity distribution and genotype-phenotype discordance in Black Americans. Clin Pharmacol Ther 2002; 72: 76–89
Evans WE, Relling MV, Rahman A, et al. Genetic basis for a lower prevalence of deficient CYP2D6 oxidative drug metabolism phenotypes in Black Americans. J Clin Invest 1993; 91: 2150–4
Relling MV, Cherrie J, Schell MJ, et al. Lower prevalence of the debrisoquin oxidative poor metabolizer phenotype in American Black versus White subjects. Clin Pharmacol Ther 1991; 50: 308–13
Jorge LF, Eichelbaum M, Griese EU, et al. Comparative evolutionary pharmacogenetics of CYP2D6 in Ngawbe and Embera Amerindians of Panama and Colombia: role of selection versus drift in world populations. Pharmacogenetics 1999; 9: 217–28
Griese EU, Zanger UM, Brudermanns U, et al. Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population. Pharmacogenetics 1998; 8: 15–26
London SJ, Daly AK, Leathart JB, et al. Genetic polymorphism of CYP2D6 and lung cancer risk in African-Americans and Caucasians in Los Angeles County. Carcinogenesis 1997; 18: 1203–14
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
Agundez JA, Ledesma MC, Ladero JM, et al. Prevalence of CYP2D6 gene duplication and its repercussion on the oxidative phenotype in a White population. Clin Pharmacol Ther 1995; 57: 265–9
Bernal ML, Sinues B, Johansson I, et al. Ten percent of North Spanish individuals carry duplicated or triplicated CYP2D6 genes associated with ultrarapid metabolism of debrisoquine. Pharmacogenetics 1999; 9: 657–60
Aynacioglu AS, Sachse C, Bozkurt A, et al. Low frequency of defective alleles of cytochrome P450 enzymes 2C19 and 2D6 in the Turkish population. Clin Pharmacol Ther 1999; 66: 185–92
McLellan RA, Oscarson M, Seidegard J, et al. Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians. Pharmacogenetics 1997; 7: 187–91
Lin KM, Finder E. Neuroleptic dosage for Asians. Am J Psychiatry 1983; 140: 490–5
Mihara K, Otani K, Suzuki A, et al. Relationship between the CYP2D6 genotype and the steady-state plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine. Psychopharmacology (Berl) 1997; 133: 95–8
Horowitz JD, Button IK, Wing L. Is perhexiline essential for the optimal management of angina pectoris? Aust N Z J Med 1995; 25: 111–3
Ashrafian H, Horowitz JD, Frenneaux MP. Perhexiline. Cardiovasc Drug Rev 2007; 25: 76–97
Cole PL, Beamer AD, McGowan N, et al. Efficacy and safety of perhexiline maleate in refractory angina: a double-blind placebo-controlled clinical trial of anovel antianginal agent. Circulation 1990; 81: 1260–70
Sorensen LB, Sorensen RN, Miners JO, et al. Polymorphic hydroxylation of perhexiline in vitro. Br J Clin Pharmacol 2003; 55: 635–8
Sallustio BC, Westley IS, Morris RG. Pharmacokinetics of the antianginal agent perhexiline: relationship between metabolic ratio and steady-state dose. Br J Clin Pharmacol 2002; 54: 107–14
Barclay ML, Sawyers SM, Begg EJ, et al. Correlation of CYP2D6 genotype with perhexiline phenotypic metabolizer status. Pharmacogenetics 2003; 13: 627–32
Cooper RG, Evans DA, Whibley EJ. Polymorphic hydroxylation of perhexiline maleate in man. J Med Genet 1984; 21: 27–33
Cooper RG, Evans DA, Price AH. Studies on the metabolism of perhexiline in man. Eur J Clin Pharmacol 1987; 32: 569–76
Morgan MY, Reshef R, Shah RR, et al. Impaired oxidation of debrisoquine in patients with perhexiline liver injury. Gut 1984; 25: 1057–64
Shah RR, Oates NS, Idle JR, et al. Impaired oxidation of debrisoquine in patients with perhexiline neuropathy. Br Med J (Clin Res Ed) 1982; 284: 295–9
Follath F. The utility of serum drug level monitoring during therapy with class III antiarrhythmic agents. J Cardiovasc Pharmacol 1992; 20 Suppl. 2: S41–3
Niwa T, Shiraga T, Mitani Y, et al. Stereoselective metabolism of cibenzoline, an antiarrhythmic drug, by human and rat liver microsomes: possible involvement ofCYP2D and CYP3A. Drug Metab Dispos 2000; 28: 1128–34
Abolfathi Z, Fiset C, Gilbert M, et al. Role of polymorphic debrisoquin 4-hydroxylase activity in the stereoselective disposition of mexiletine in humans. J Pharmacol Exp Ther 1993; 266: 1196–201
Broly F, Libersa C, Lhermitte M, et al. Inhibitory studies of mexiletine and dextromethorphan oxidation in human liver microsomes. Biochem Pharmacol 1990; 39: 1045–53
Botsch S, Gautier JC, Beaune P, et al. Identification and characterization of the cytochrome P450 enzymes involved in N-dealkylation of propafenone: molecular base for interaction potential and variable disposition of active metabolites. Mol Pharmacol 1993;43: 120–6
Kroemer HK, Fischer C, Meese CO, et al. Enantiomer/enantiomer interaction of (S)- and (R)-propafenone for cytochrome P450IID6-catalyzed 5-hydroxylation: in vitro evaluation of the mechanism. Mol Pharmacol 1991; 40: 135–42
Kroemer HK, Mikus G, Kronbach T, et al. In vitro characterization of the human cytochrome P-450 involved in polymorphic oxidation of propafenone. Clin Pharmacol Ther 1989; 45: 28–33
Funck-Brentano C, Thomas G, Jacqz-Aigrain E, et al. Polymorphism of dextromethorphan metabolism: relationships between phenotype, genotype and response to the administration of encainide in humans. J Pharmacol Exp Ther 1992; 263: 780–6
Haefeli WE, Bargetzi MJ, Follath F, et al. Potent inhibition of cytochrome P450IID6 (debrisoquin 4-hydroxylase) by flecainide in vitro and in vivo. J Cardiovasc Pharmacol 1990; 15: 776–9
Mehvar R, Brocks DR, Vakily M. Impact of stereoselectivity on the pharmacokinetics and pharmacodynamics of antiarrhythmic drugs. Clin Pharmacokinet 2002; 41: 533–58
Turgeon J, Roden DM. Pharmacokinetic profile of encainide. Clin Pharmacol Ther 1989; 45: 692–4
Carey Jr EL, Duff HJ, Roden DM, et al. Encainide and its metabolites: comparative effects in man on ventricular arrhythmia and electrocardiographic intervals. J Clin Invest 1984; 73: 539–47
Barbey JT, Thompson KA, Echt DS, et al. Antiarrhythmic activity, electrocardiographic effects and pharmacokinetics of the encainide metabolites O-desmethyl encainide and 3-methoxy-O-desmethyl encainide in man. Circulation 1988; 77: 380–91
Roden DM, Wood AJ, Wilkinson GR, et al. Disposition kinetics of encainide and metabolites. Am J Cardiol 1986; 58: 4–9C
McAllister CB, Wolfenden HT, Aslanian WS, et al. Oxidative metabolism of encainide: polymorphism, pharmacokinetics and clinical considerations. Xenobiotica 1986; 16: 483–90
Woosley RL, Roden DM, Dai GH, et al. Co-inheritance of the polymorphic metabolism of encainide and debrisoquin. Clin Pharmacol Ther 1986; 39: 282–7
Wang T, Roden DM, Wolfenden HT, et al. Influence of genetic polymorphism on the metabolism and disposition of encainide in man. J Pharmacol Exp Ther 1984; 228: 605–11
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
Zhou HH, Wood AJ. Stereoselective disposition of carvedilol is determined by CYP2D6. Clin Pharmacol Ther 1995; 57: 518–24
Giessmann T, Modess C, Hecker U, et al. CYP2D6 genotype and induction of intestinal drug transporters by rifampin predict presystemic clearance of carvedilol in healthy subjects. Clin Pharmacol Ther 2004; 75: 213–22
Yasuda SU, Wellstein A, Likhari P, et al. Chlorpheniramine plasma concentration and histamine H1-receptor occupancy. Clin Pharmacol Ther 1995; 58: 210–20
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
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
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
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
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
Spina E, Steiner E, Ericsson O, et al. Hydroxylation of desmethylimipramine: dependence on the debrisoquin hydroxylation phenotype. Clin Pharmacol Ther 1987; 41: 314–9
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
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
Brosen K, Hansen JG, Nielsen KK, et al. Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur J Clin Pharmacol 1993; 44: 349–55
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
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
Gross AS, Mikus G, Fischer C, et al. Polymorphic flecainide disposition under conditions of uncontrolled urine flow and pH. EurJ Clin Pharmacol 1991; 40: 155–62
Mikus G, Gross AS, Beckmann J, et al. The influence of the sparteine/debrisoquin phenotype on the disposition of flecainide. Clin Pharmacol Ther 1989; 45: 562–7
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
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
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
Brosen K, Otton SV, Gram LF. Imipramine demethylation and hydroxylation: impact of the sparteine oxidation phenotype. Clin Pharmacol Ther 1986; 40: 543–9
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
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
Lennard MS, Tucker GT, Silas JH, et al. Differential stereoselective metabolism of metoprolol in extensive and poor debrisoquin metabolizers. Clin Pharmacol Ther 1983; 34: 732–7
Hamelin BA, Bouayad A, Methot J, et al. Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity. Clin Pharmacol Ther 2000; 67: 466–77
Lennard MS, Silas JH, Freestone S, et al. Defective metabolism of metoprolol in poor hydroxylators of debrisoquine. Br J Clin Pharmacol 1982; 14: 301–3
Broly F, Vandamme N, Libersa C, et al. The metabolism of mexiletine in relation to the debrisoquine/sparteine-type polymorphism of drug oxidation. Br J Clin Pharmacol 1991; 32: 459–66
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
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
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
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
Sindrup SH, Brosen K, Gram LF, et al. The relationship between paroxetine and the sparteine oxidation polymorphism. Clin Pharmacol Ther 1992; 51: 278–87
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
Pollock BG, Mulsant BH, Sweet RA, et al. Prospective cytochrome P450 phenotyping for neuroleptic treatment in dementia. Psychopharmacol Bull 1995; 31: 327–31
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
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
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
Labbe L, O’Hara G, Lefebvre M, et al. Pharmacokinetic and pharmacodynamic interaction between mexiletine and propafenone in human beings. Clin Pharmacol Ther 2000; 68: 44–57
Cai WM, Chen B, Cai MH, et al. The influence of CYP2D6 activity on the kinetics of propafenone enantiomers in Chinese subjects. Br J Clin Pharmacol 1999; 47: 553–6
Siddoway LA, Thompson KA, McAllister CB, et al. Polymorphism of propafenone metabolism and disposition in man: clinical and pharmacokinetic consequences. Circulation 1987; 75: 785–91
Dilger K, Greiner B, Fromm MF, et al. Consequences of rifampicin treatment on propafenone disposition in extensive and poor metabolizers of CYP2D6. Pharmacogenetics 1999; 9: 551–9
Lee JT, Kroemer HK, Silberstein DJ, et al. The role of genetically determined polymorphic drug metabolism in the b-blockade produced by propafenone. N Engl J Med 1990; 322: 1764–8
Chen B, Cai WM. Influence of CYP2D6*10B genotype on pharmacokinetics of propafenone enantiomers in Chinese subjects. Acta Pharmacol Sin 2003; 24: 1277–80
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
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
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
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
van der Weide J, van Baalen-Benedek EH, Kootstra-Ros JE. Metabolic ratios of psychotropics as indication of cytochrome P450 2D6/2C19 genotype. Ther Drug Monit 2005; 27: 478–83
Leon J, Susce MT, Pan RM, et al. A study of genetic (CYP2D6 and ABCB1) and environmental (drug inhibitors and inducers) variables that may influence plasma risperidone levels. Pharmacopsychiatry 2007; 40: 93–102
Jin Y, Desta Z, Stearns V, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 2005; 97: 30–9
Schroth W, Antoniadou L, Fritz P, et al. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol 2007; 25: 5187–93
Goetz MP, Knox SK, Suman VJ, et al. The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat 2007; 101: 113–21
Bonanni B, Macis D, Maisonneuve P, et al. Polymorphism in the CYP2D6 tamoxifen-metabolizing gene influences clinical effect but not hot flashes: data from the Italian Tamoxifen Trial. J Clin Oncol 2006; 24: 3708–9; author reply 3709
Borges S, Desta Z, Li L, et al. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol Ther 2006; 80: 61–74
Goetz MP, Rae JM, Suman VJ, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005; 23: 9312–8
Lim HS, Ju Lee H, Seok Lee K, et al. Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol 2007; 25: 3837–45
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
Lewis RV, Lennard MS, Jackson PR, et al. Timolol and atenolol: relationships between oxidation phenotype, pharmacokinetics and pharmacodynamics. Br J Clin Pharmacol 1985; 19: 329–33
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
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
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
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
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
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
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
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
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
Roden DM, Woosley RL. Clinical pharmacokinetics of encainide. Clin Pharmacokinet 1988; 14: 141–7
Anderson JL, Stewart JR, Perry BA, et al. Oral flecainide acetate for the treatment of ventricular arrhythmias. N Engl J Med 1981; 305: 473–7
McQuinn RL, Quarfoth GJ, Johnson JD, et al. Biotransformation and elimination of 14C-flecainide acetate in humans. Drug Metab Dispos 1984; 12: 414–20
Gross AS, Mikus G, Fischer C, et al. Stereoselective disposition of flecainide in relation to the sparteine/debrisoquine metaboliser phenotype. Br J Clin Pharmacol 1989; 28: 555–66
Doki K, Homma M, Kuga K, et al. Effect of CYP2D6 genotype on flecainide pharmacokinetics in Japanese patients with supraventricular tachyarrhythmia. Eur J Clin Pharmacol 2006; 62: 919–26
Martinez-Selles M, Castillo I, Montenegro P, et al. Pharmacogenetic study of the response to flecainide and propafenone in patients with atrial fibrillation [in Spanish]. Rev Esp Cardiol 2005; 58: 745–8
Funck-Brentano C, Becquemont L, Kroemer HK, et al. Variable disposition kinetics and electrocardiographic effects of flecainide during repeated dosing in humans: contribution of genetic factors, dose-dependent clearance, and interaction with amiodarone. Clin Pharmacol Ther 1994; 55: 256–69
Tenneze L, Tarral E, Ducloux N, et al. Pharmacokinetics and electrocardiographic effects of a new controlled-release form of flecainide acetate: comparison with the standard form and influence of the CYP2D6 polymorphism. Clin Pharmacol Ther 2002; 72: 112–22
Birgersdotter UM, Wong W, Turgeon J, et al. Stereoselective genetically-determined interaction between chronic flecainide and quinidine in patients with arrhythmias. Br J Clin Pharmacol 1992; 33: 275–80
Lim KS, Cho JY, Jang IJ, et al. Pharmacokinetic interaction of flecainide and paroxetine in relation to the CYP2D6*10 allele in healthy Korean subjects. Br J Clin Pharmacol 2008; 66: 660–6
Monk JP, Brogden RN. Mexiletine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in the treatment of arrhythmias. Drugs 1990; 40: 374–411
Vandamme N, Broly F, Libersa C, et al. Stereoselective hydroxylation of mexiletine in human liver microsomes: implication of P450IID6: a preliminary report. J Cardiovasc Pharmacol 1993; 21: 77–83
Beckett AH, Chidomere EC. The identification and analysis of mexiletine and its metabolic products in man. J Pharm Pharmacol 1977; 29: 281–5
Turgeon J, Fiset C, Giguere R, et al. Influence of debrisoquine phenotype and of quinidine on mexiletine disposition in man. J Pharmacol Exp Ther 1991; 259: 789–98
Broly F, Vandamme N, Caron J, et al. Single-dose quinidine treatment in hibits mexiletine oxidation in extensive metabolizers of debrisoquine. Life Sci 1991;48:PL123–8
Turgeon J, Pare JR, Lalande M, et al. Isolation and structural characterization by spectroscopic methods of two glucuronide metabolites of mexiletine after N-oxidation and deamination. Drug Metab Dispos 1992; 20: 762–9
Klein A, Sami M, Selinger K. Mexiletine kinetics in healthy subjects taking cimetidine. Clin Pharmacol Ther 1985; 37: 669–73
Brockmeyer NH, Breithaupt H, Ferdinand W, et al. Kinetics of oral and intravenous mexiletine: lack of effect of cimetidine and ranitidine. Eur J Clin Pharmacol 1989; 36: 375–8
Yonezawa E, Matsumoto K, Ueno K, et al. Lack of interaction between amiodarone and mexiletine in cardiac arrhythmia patients. J Clin Pharmacol 2002; 42: 342–6
Ueno K, Yamaguchi R, Tanaka K, et al. Lack of akinetic interaction between fluconazole and mexiletine. Eur J Clin Pharmacol 1996; 50: 129–31
Kusumoto M, Ueno K, Tanaka K, et al. Lack of pharmacokinetic interaction between mexiletine and omeprazole. Ann Pharmacother 1998; 32: 182–4
Bryson HM, Palmer KJ, Langtry HD, et al. Propafenone: a reappraisal of its pharmacology, pharmacokinetics and therapeutic use in cardiac arrhythmias. Drugs 1993;45:85–130
Kroemer HK, Funck-Brentano C, Silberstein DJ, et al. Stereoselective disposition and pharmacologic activity of propafenone enantiomers. Circulation 1989; 79: 1068–76
Hege HG, Hollmann M, Kaumeier S, et al. The metabolic fate of 2H-labelled propafenone in man. Eur J Drug Metab Pharmacokinet 1984; 9: 41–55
Zhou Q, Yao TW, Yu YN, et al. Concentration dependent stereoselectivity of propafenone N-depropylation metabolism with human hepatic recombinant CYP1A2. Pharmazie 2003; 58: 651–3
Funck-Brentano C, Turgeon J, Woosley RL, et al. Effect of low dose quinidine on encainide pharmacokinetics and pharmacodynamics: influence of genetic polymorphism. J Pharmacol Exp Ther 1989; 249: 134–42
Capucci A, Boriani G, Marchesini B, et al. Minimal effective concentration values of propafenone and 5-hydroxy-propafenone in acute and chronic therapy. Cardiovasc Drugs Ther 1990; 4: 281–7
Anzenbacherova E, Anzenbacher P, Perlik F, et al. Use of a propafenone metabolic ratio as a measure of CYP2D6 activity. Int J Clin Pharmacol Ther 2000; 38: 426–9
Jazwinska-Tarnawska E, Orzechowska-Juzwenko K, Niewinski P, et al. The influence of CYP2D6 polymorphism on the antiarrhythmic efficacy of propafenone in patients with paroxysmal atrial fibrillation during 3 months propafenone prophylactic treatment. Int J Clin Pharmacol Ther 2001; 39: 288–92
Morike KE, Roden DM. Quinidine-enhanced beta-blockade during treatment with propafenone in extensive metabolizer human subjects. Clin Pharmacol Ther 1994; 55: 28–34
Morike K, Magadum S, Mettang T, et al. Propafenone in a usual dose produces severe side-effects: the impact of genetically determined metabolic status on drug therapy. J Intern Med 1995; 238: 469–72
Ujhelyi MR, O’Rangers EA, Fan C, et al. The pharmacokinetic and pharmacodynamic interaction between propafenone and lidocaine. Clin Pharmacol Ther 1993; 53: 38–48
Kowey PR, Kirsten EB, Fu CH, et al. Interaction between propranolol and propafenone in healthy volunteers. J Clin Pharmacol 1989; 29: 512–7
Wagner F, Kalusche D, Trenk D, et al. Drug interaction between propafenone and metoprolol. Br J Clin Pharmacol 1987; 24: 213–20
Katz MR. Raised serum levels of desipramine with the antiarrhythmic propafenone. J Clin Psychiatry 1991; 52: 432–3
Cai WM, Chen B, Zhou Y, et al. Fluoxetine impairs the CYP2D6-mediated metabolism of propafenone enantiomers in healthy Chinese volunteers. Clin Pharmacol Ther 1999; 66: 516–21
Roy D, Pratt CM, Torp-Pedersen C, et al. Vernakalant hydrochloride for rapid conversion of atrial fibrillation: a phase 3, randomized, placebo-controlled trial. Circulation 2008; 117: 1518–25
Naccarelli GV, Wolbrette DL, Samii S, et al. Vernakalant: pharmacology electrophysiology, safety and efficacy. Drugs Today (Barc) 2008; 44: 325–9
Cardiome Pharma Corporation [online]. Available from URL: http://cardiome.com/Vernakalant.php [Accessed 2009 Sep 30]
Mao ZL, Wheeler JJ, Clohs L, et al. Pharmacokinetics of novel atrial-selective antiarrhythmic agent vernakalant hydrochloride injection (RSD1235): influence ofCYP2D6 expression and other factors. J Clin Pharmacol 2009; 49: 17–29
Mehvar R, Brocks DR. Stereospecific pharmacokinetics and pharmacodynamics of β-adrenergic blockers in humans. J Pharm Pharm Sci 2001; 4: 185–200
Oldham HG, Clarke SE. In vitro identification of the human cytochrome P450 enzymes involved in the metabolism of R(+)- and S(−)-carvedilol. Drug Metab Dispos 1997; 25: 970–7
Narimatsu S, Takemi C, Tsuzuki D, et al. Stereoselective metabolism of bufuralol racemate and enantiomers in human liver microsomes. J Pharmacol Exp Ther 2002; 303: 172–8
Mautz DS, Nelson WL, Shen DD. Regioselective and stereoselective oxidation of metoprolol and bufuralol catalyzed by microsomes containing cDNA-expressed human P4502D6. Drug Metab Dispos 1995; 23: 513–7
McGourty JC, Silas JH, Lennard MS, et al. Metoprolol metabolism and debrisoquine oxidation polymorphism: population and family studies. Br J Clin Pharmacol 1985; 20: 555–66
Belpaire FM, Wijnant P, Temmerman A, et al. The oxidative metabolism of metoprolol in human liver microsomes: inhibition by the selective serotonin reuptake inhibitors. Eur J Clin Pharmacol 1998; 54: 261–4
Tassaneeyakul W, Birkett DJ, Veronese ME, et al. Specificity of substrate and inhibitor probes for human cytochromes P450 1A1 and 1A2. J Pharmacol Exp Ther 1993; 265: 401–7
Masubuchi Y, Hosokawa S, Horie T, et al. Cytochrome P450 isozymes involved in propranolol metabolism in human liver microsomes: the role of CYP2D6 as ring-hydroxylase and CYP1A2 as N-desisopropylase. Drug Metab Dispos 1994; 22: 909–15
Johnson JA, Herring VL, Wolfe MS, et al. CYP1A2 and CYP2D6 4-hydroxy-late propranolol and both reactions exhibit racial differences. J Pharmacol Exp Ther 2000; 294: 1099–105
Volotinen M, Turpeinen M, Tolonen A, et al. Timolol metabolism in human liver microsomes is mediated principally by CYP2D6. Drug Metab Dispos 2007;35: 1135–41
McTavish D, Campoli-Richards D, Sorkin EM. Carvedilol: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 1993; 45: 232–58
Keating GM, Jarvis B. Carvedilol: a review of its use in chronic heart failure. Drugs 2003; 63: 1697–741
Neugebauer G, Akpan W, Kaufmann B, et al. Stereoselective disposition of carvedilol in man after intravenous and oral administration of the racemic compound. Eur J Clin Pharmacol 1990; 38 Suppl. 2: S108–11
Honda M, Nozawa T, Igarashi N, et al. Effect of CYP2D6*10 on the pharmacokinetics of R- and S-carvedilol in healthy Japanese volunteers. Biol Pharm Bull 2005; 28: 1476–9
Prakash A, Markham A. Metoprolol: a review of its use in chronic heart failure. Drugs 2000; 60: 647–78
Dayer P, Leemann T, Marmy A, et al. Interindividual variation of β-adrenoceptor blocking drugs, plasma concentration and effect: influence of genetic status on behaviour of atenolol, bopindolol and metoprolol. Eur J Clin Pharmacol 1985; 28: 149–53
Borg KO, Carlsson E, Hoffmann KJ, et al. Metabolism of metoprolol-(3-h) in man, the dog and the rat. Acta Pharmacol Toxicol (Copenh) 1975;36: 125–35
Otton SV, Crewe HK, Lennard MS, et al. Use of quinidine inhibition to define the role of the sparteine/debrisoquine cytochrome P450 in metoprolol oxidation by human liver microsomes. J Pharmacol Exp Ther 1988; 247: 242–7
Johnson JA, Burlew BS. Metoprolol metabolism via cytochrome P4502D6 in ethnic populations. Drug Metab Dispos 1996; 24: 350–5
Hoffmann KJ, Regardh CG, Aurell M, et al. The effect of impaired renal function on the plasma concentration and urinary excretion of metoprolol metabolites. Clin Pharmacokinet 1980; 5: 181–91
Hemeryck A, Lefebvre RA, De Vriendt C, et al. Paroxetine affects metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharmacol Ther 2000; 67: 283–91
Hemeryck A, De Vriendt CA, Belpaire FM. Metoprolol-paroxetine interaction in human livermicrosomes: stereoselective aspects and prediction of the in vivo interaction. Drug Metab Dispos 2001; 29: 656–63
Kim M, Shen DD, Eddy AC, et al. Inhibition of the enantioselective oxidative metabolism of metoprolol by verapamil in human liver microsomes. Drug Metab Dispos 1993; 21: 309–17
Seeringer A, Brockmoller J, Bauer S, et al. Enantiospecific pharmacokinetics of metoprolol in CYP2D6 ultra-rapid metabolizers and correlation with exercise-induced heart rate. Eur J Clin Pharmacol 2008; 64: 883–8
Wuttke H, Rau T, Heide R, et al. Increased frequency of cytochrome P450 2D6 poor metabolizers among patients with metoprolol-associated adverse effects. Clin Pharmacol Ther 2002; 72: 429–37
Zineh I, Beitelshees AL, Gaedigk A, et al. Pharmacokinetics and CYP2D6 genotypes do not predict metoprolol adverse events or efficacy in hypertension. Clin Pharmacol Ther 2004; 76: 536–44
Fux R, Morike K, Prohmer AM, et al. Impact of CYP2D6 genotype on adverse effects during treatment with metoprolol: a prospective clinical study. Clin Pharmacol Ther 2005; 78: 378–87
Bijl MJ, Visser LE, van Schaik RH, et al. Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in β-blocker users. Clin Pharmacol Ther 2009; 85: 45–50
Talaat RE, Nelson WL. Regioisomeric aromatic dihydroxylation of propranolol: synthesis and identification of 4,6- and 4,8-dihydroxypropranolol as metabolites in the rat and in man. Drug Metab Dispos 1988; 16: 212–6
Ward SA, Walle T, Walle UK, et al. Propranolol’s metabolism is determined by both mephenytoin and debrisoquin hydroxylase activities. Clin Pharmacol Ther 1989; 45: 72–9
Lennard MS, Jackson PR, Freestone S, et al. The relationship between debrisoquine oxidation phenotype and the pharmacokinetics and pharmacodynamics of propranolol. BrJClin Pharmacol 1984; 17: 679–85
Lennard MS, Tucker GT, Silas JH, et al. Debrisoquine polymorphism and the metabolism and action of metoprolol, timolol, propranolol and atenolol. Xenobiotica 1986; 16: 435–47
Raghuram TC, Koshakji RP, Wilkinson GR, et al. Polymorphic ability to metabolize propranolol alters 4-hydroxypropranolol levels but not β-blockade. Clin Pharmacol Ther 1984; 36: 51–6
Lennard MS, Jackson PR, Freestone S, et al. The oral clearance and β-adrenoceptor antagonist activity of propranolol after single dose are not related to debrisoquine oxidation phenotype. Br J Clin Pharmacol 1984; 17 Suppl. 1: 106–7S
Sowinski KM, Burlew BS. Impact of CYP2D6 poor metabolizer phenotype on propranolol pharmacokinetics and response. Pharmacotherapy 1997; 17: 1305–10
Shaheen O, Biollaz J, Koshakji RP, et al. Influence of debrisoquin phenotype on the inducibility of propranolol metabolism. Clin Pharmacol Ther 1989; 45: 439–43
Lai ML, Wang SL, Lai MD, et al. Propranolol disposition in Chinese subjects of different CYP2D6 genotypes. Clin Pharmacol Ther 1995; 58: 264–8
Zhou HH, Anthony LB, Roden DM, et al. Quinidine reduces clearance of (+)-propranolol more than (−)-propranolol through marked reduction in 4-hydroxylation. Clin Pharmacol Ther 1990; 47: 686–93
Frishman WH, Fuksbrumer MS, Tannenbaum M. Topical ophthalmic β-adrenergic blockade for the treatment of glaucoma and ocular hypertension. J Clin Pharmacol 1994; 34: 795–803
Heel RC, Brogden RN, Speight TM, et al. Timolol: a review of its therapeutic efficacy in the topical treatment of glaucoma. Drugs 1979; 17: 38–55
Nieminen T, Lehtimaki T, Maenpaa J, et al. Ophthalmic timolol: plasma concentration and systemic cardiopulmonary effects. Scand J Clin Lab Invest 2007; 67: 237–45
Lama PJ. Systemic adverse effects of β-adrenergic blockers: an evidence-based assessment. Am J Ophthalmol 2002; 134: 749–60
Vander Zanden JA, Valuck RJ, Bunch CL, et al. Systemic adverse effects of ophthalmic β-blockers. Ann Pharmacother 2001; 35: 1633–7
Kaila T, Huupponen R, Karhuvaara S, et al. Beta-blocking effects of timolol at low plasma concentrations. Clin Pharmacol Ther 1991; 49: 53–8
Huupponen R, Kaila T, Lahdes K, et al. Systemic absorption of ocular timolol in poor and extensive metabolizers of debrisoquine. J Ocul Pharmacol 1991; 7: 183–7
Nieminen T, Uusitalo H, Maenpaa J, et al. Polymorphisms of genes CYP2D6, ADRB1 and GNAS1 in pharmacokinetics and systemic effects of ophthalmic timolol: a pilot study. Eur J Clin Pharmacol 2005; 61: 811–9
Edeki TI, He H, Wood AJ. Pharmacogenetic explanation for excessive betablockade following timolol eye drops: potential for oral-ophthalmic drug interaction. JAMA 1995; 274: 1611–3
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No sources of funding were used to assist in the preparation of this review. The author has no conflicts of interest that are directly relevant to the content of this review.
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Zhou, SF. Polymorphism of Human Cytochrome P450 2D6 and Its Clinical Significance. Clin Pharmacokinet 48, 689–723 (2009). https://doi.org/10.2165/11318030-000000000-00000
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DOI: https://doi.org/10.2165/11318030-000000000-00000