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