TABLE 3

Difference in drug concentrations with CYP2D6 metabolizer status and evidence for and against genotyping Only studies involving oral drug administration and adult subjects were included. Case reports were excluded. AUC differences were significant unless otherwise specified. Cp12 h (concentration at 12 h post-dose) or Cpmin (trough concentration) were used only if AUC data were not available. No differentiation is made between *1 and *2 alleles. Heterozygous (het) EM is used when one high-activity allele and one-low activity allele (e.g., *1/*3) are present. PM refers to two low-activity alleles or a poor metabolizer phenotype. EM refers to combined het EM and homozygous (hom) EM, either known (genotype) or presumed (phenotype).

Drug Approximate Difference in Mean/Median Concentrations (AUC) between PMs and EMs, Unless Otherwise Specified Evidence for Genotyping Evidence against Genotyping References for Pharmacokinetic Data
Atomoxetine Repeated dosing: 8-fold More side effects (e.g., tremor), greater weight loss and increase in pulse rate in PMs Discontinuation rates do not differ between PMs and EMs Sauer et al. (2003)
Carvedilol Single dose: 2.6-fold for R-carvedilol (nonsignificant increase for S-carvedilol); repeated dosing: ∼2-fold for racemic, R-, and S-carvedilol Multiple metabolic pathways to multiple active metabolites; high therapeutic index; differential α and β effects between enantiomers of parent drug complicates interpretation Zhou and Wood (1995); Giessmann et al. (2004)
Chlorpheniramine Single dose: 3.2- and 2.4-fold for S- and R-chlorpheniramine, respectively Clinical implications unclear Yasuda et al. (2002)
Chlorpromazine Single dose: nonsignificant increase in *10/*10 and *1/*10, cf. hom EM Multiple metabolic pathways to at least one active metabolite Sunwoo et al. (2004)
Clomipramine Single dose: 2-fold; repeated dosing: (Cp∼12 h) 1.6- to 3.7-fold for desmethylclomipramine and 1.6- to 3.4-fold for clomipramine + desmethylclomipramine (nonsignificant increase in clomipramine) Multiple metabolic pathways to multiple active metabolites; little evidence for altered effect Sindrup et al. (1990b); Kramer Nielsen et al. (1992, 1994); Gram et al. (1999)
Codeine Single dose and repeated dosing: no difference in parent (inactive) but undetectable/very low morphine concentrations in PMs Convincing evidence for lack of analgesia in healthy volunteers Data in patients lacking Desmeules et al. (1991); Yue et al. (1991); Caraco et al. (1996); Poulsen et al. (1996b); Eckhardt et al. (1998)
Desipramine Single dose: 4- to 8-fold; repeated dosing: (Cp; time unknown) 3- to 4.5-fold (*10/*5 + *10/*10), 1.5-fold (*1/*10), cf. hom EM Active metabolites; concentration-effect relationship undefined for this drug; evidence for altered outcomes limited Brosen et al. (1986a, 1993a); Spina et al. (1987, 1997b); Steiner and Spina (1987); Shimoda et al. (2000b)
Dihydrocodeine Single dose: no difference in parent (inactive) but dihydromorphine concentrations in PMs 0.15-fold of EM Clinical implications unclear Fromm et al. (1995)
Doxepin Single dose: 2.9-fold (PM), cf. hom EM for doxepin + desmethyldoxepin (no significant difference between hom and het EM) Multiple metabolic pathways to multiple active metabolites; little evidence for altered effect Kirchheiner et al. (2002d)
Flecainide Single dose: 1.7-, 2.4-, and 3.6-fold for racemic, R- and S-flecainide, respectively; repeated dosing: no difference Substantial pH dependent renal elimination; no important concentration differences at steady-state Mikus et al. (1989); Gross et al. (1991); Tenneze et al. (2002)
Fluoxetine Single dose: 3.9-, 11.5-, and 2.4-fold for racemic, S- and R-fluoxetine, respectively [0.5-fold for racemic norfluoxetine (difference for enantiomers N.S. for norfluoxetine)]; repeated dosing: (Cpmin) 2.3- and 0.3-fold for S-fluoxetine and S-norfluoxetine, respectively (no significant difference in R-fluoxetine or R-norfluoxetine) Sum of active moiety does not vary importantly between EMs and PMs; concentration-effect relationship ill-defined for the SSRIs; autophenocopying occurs Hamelin et al. (1996); Fjordside et al. (1999); Eap et al. (2001); Scordo et al. (2005)
Imipramine Single dose: 9.1-fold for desipramine (nonsignificant increase for imipramine); repeated dosing: (Cp12 h) 2.2-, 6.8-, and 4.8-fold for imipramine, desipramine, and imipramine + desipramine, respectively Multiple metabolic pathways to multiple active metabolites; little evidence for altered effect with CYP2D6 status; concentration-effect relationship ill-defined for this drug Brosen et al. (1986a); Koyama et al. (1994)
Maprotiline Repeated dosing: 3.5-fold Metabolized by multiple enzymes to multiple active metabolites Firkusny and Gleite (1994)
Metoprolol Single dose: 4- to 8-fold (PM), 0.5-fold (UM); 2.6, 2.5-, and 3.2-fold (*10/*10); 1.4-, 1.3-, and 1.4- fold (*1/*10), cf. hom EM for racemic, S-, and R- metoprolol, respectively; repeated dosing: 3- to 4- fold; 2.4-fold (het EM), cf. hom EM Evidence for gene-effect relationship in healthy volunteers High therapeutic index; CYP2D6 status does not appear to significantly influence adverse effects in patients Freestone et al. (1982); Lennard et al. (1982a,b); Deroubaix et al. (1996); Koytchev et al. (1998); Huang et al. (1999); Hamelin et al. (2000); Kirchheiner et al. (2004a)
Mexiletine Single dose: 2.0- to 2.3-, 1.4- to 2.1-, and 1.6- to 2.2-fold for racemic, R-, and S- mexiletine, respectively Multiple pathways of elimination; no evidence of clinical effects pH-dependent renal elimination Broly et al. (1991); Turgeon et al. (1991); Abolfathi et al. (1993); Labbe et al., 1999
Mianserin Single dose: 1.8- and 1.5-fold for mianserin and desmethylmianserin, respectively; repeated dosing: (Cp~12 h) no difference, cf. hom EM for S- or R-mianserin or desmethylmianserin Multiple metabolic pathways to multiple active metabolites; no evidence of clinical effect Dahl et al. (1994); Mihara et al. (1997); Eap et al. (1998)
Nortriptyline Single dose: 3.3-fold (PM), 2.8-fold (het EM), cf. hom EMs; nonsignificant decrease in ultrarapid metabolizers; 2.2-fold (*10/*10), 1.4-fold (*1/*10), cf. hom EM; repeated dosing: 2.1-fold (*10/*5 + *10/*10), cf. hom EM Reasonable concentration-effect relationship, i.e., `established' therapeutic range 10-Hydroxynortriptyline (active) has reciprocal changes; evidence for clinical effects lacking Dalen et al. (1998, 2003); Yue et al. (1998); Morita et al. (2000)
Paroxetine Single dose: 7.1-fold; 3.4-fold (*10/*10); 4-fold (*1/*10, N.S.), cf. hom EM; repeated dosing: 1.7-fold Autophenocopying occurs; limited data on clinical effect; concentration-effect relationship ill-defined for this class Sindrup et al. (1992c); Yoon et al. (2000)
Perhexiline Single dose: (Cp24 h) 6-fold Toxicity higher in PMs; concentration-effect relationship established; low therapeutic index Saturable metabolism Cooper et al. (1984)
Perphenazine Single dose: 4.1-fold; repeated dosing: (Cp8–16 h) 2-fold Possible increase in adverse effects in PMs Active metabolite not measured Dahl-Puustinen et al. (1989); Linnet and Wiborg (1996b)
Propafenone Single dose: 7.9-fold; repeated dosing: 7-, 0.2-, 4.3-, and 4.8-fold for racemic parent, 5-hydroxypropafenone, and R- and S-propafenone, respectively Possible increase in adverse effects in PMs Multiple metabolic pathways; active metabolite has reciprocal changes; enantiomers have different effects Kroemer et al. (1989a); Dilger et al. (1999); Labbe et al. (2000)
Risperidone Repeated dosing: 4.8- and 0.5-fold for risperidone and 9-hydroxyrisperidone, respectively May be more problems at extremes of CYP2D6 activity Sum of active moiety does not vary importantly between EMs and PMs Bondolfi et al. (2002)
Thioridazine Single dose: 4.5- and 1.4-fold for thioridazine and thioridazine + mesoridazine + sulforidazine, respectively Multiple metabolic pathways to multiple active metabolites; autophenocopying occurs; enantiomers have different effects von Bahr et al. (1991)
Timolol Single dose: 2- to 4-fold PM volunteers may have increased and prolonged effects Lewis et al. (1985); McGourty et al. (1985a)
Tolterodine Repeated dosing: 10-fold for tolterodine (5-hydroxymethyltolterodine unquantifiable in PMs); 30-fold (PM), 4.4-fold (het EM), cf. hom EM Sum of active moieties does not differ between PMs and EMs; alternative metabolic pathway Brynne et al. (1999c); Olsson and Szamosi (2001b)
Tramadol Single dose: 1.2-, 1.3-, and 0.5-fold for (+)-tramadol, (–)-tramadol, and (–)-desmethyltramadol, respectively; (+)-desmethyltramadol ≤ detection limit in PMs Active metabolite has major opioid effect; possibly greater opioid effect in PMs Poulsen et al. (1996a)
Tropisetron Single dose: 6.9-fold; 6.8-fold (*10/*5 + *10/*10), 1.9-fold (*1/*10), 0.5-fold (UM), cf. hom EM Little evidence for altered effect; high therapeutic index de Bruijn (1992); Kim et al. (2003)
Venlafaxine Single dose: 2.3- and 0.3-fold for venlafaxine and desmethylvenlafaxine, respectively; 6-fold (*10/*5 + *10/*10), 2-fold (*1/*10, N.S. in one study), cf. hom EM for venlafaxine; repeated dosing: 3.4- to 3.9-fold for venlafaxine Multiple metabolic pathways to multiple metabolites; sum of active moieties does not change significantly; enantiomers have different activities Fukuda et al. (1999, 2000); Lessard et al. (1999, 2001); Lindh et al. (2003)
Zuclopenthixol Single dose: 1.9-fold; repeated dosing: (Cp12 h) 1.6-fold No evidence of clinical effects Dahl et al. (1991); Linnet and Wiborg (1996a)
  • N.S., not significant