Difference in drug concentrations with CYP2C19 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 postdose) or Cpmin (trough concentration) were used only if AUC data were not available. 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 metaboliser phenotype. EM refers to combined het and homozygous (hom) EM, either known (genotype) or presumed (phenotype).
| Drug | Approximate Difference in Mean/Median Concentrations (AUC) Compared with *1 / *1, Unless Otherwise Stated | Evidence for Genotyping | Evidence against Genotyping | References for Pharmacokinetic Data |
|---|---|---|---|---|
| Amitriptyline | Single dose: 1.4- and 0.4-fold for amitriptyline and nortriptyline, respectively; repeated dosing: (Cpmin or Cp∼11 h) 1.8-fold (PM), cf. hom EM for amitriptyline (het EM similar to hom EM); 0.4-fold (PM); 0.8-fold (het EM), cf. hom EM for nortriptyline | Reciprocal change in parent to metabolite; multiple metabolic pathways to multiple active metabolites; little evidence for altered effect with CYP2C19 status | Shimoda et al. (2002); Jiang et al. (2003); Steimer et al. (2004) | |
| Citalopram | Single dose: 1.2-fold; repeated dosing: 1.8- and 1.6-fold for racemic and S-citalopram, respectively; no difference in R-citalopram | Relatively wide therapeutic index; concentration-effect relationship ill-defined for the SSRIs | Sindrup et al. (1993); Herrlin et al. (2003); Yu et al. (2003) | |
| Clomipramine | Single dose: 1.5-fold; repeated dosing (Cp∼13 h): 1.8-fold (PM), 1.4-fold (het EM), cf. hom EM | Multiple metabolic pathways to multiple active metabolites; little evidence for altered effect with CYP2C19 status; concentration-effect relationship ill-defined | Kramer Nielsen et al. (1994); Yokono et al. (2001) | |
| Diazepam | Single dose: 1.3- to 4.3-fold and 1.9-fold for diazepam and desmethyldiazepam, respectively; 6.1- and 2.4-fold (PM), 2.5- and 1.4-fold (het EM), cf. hom EM for diazepam and desmethyldiazepam, respectively | Multiple metabolic pathways to multiple active metabolites; clinical studies lacking | Bertilsson et al. (1989); Zhang et al. (1990); Sohn et al. (1992b); Wan et al. (1996); Qin et al. (1999) | |
| Fluoxetine | Single dose: 2.9- and 0.4-fold (PM), cf. hom EM for fluoxetine and norfluoxetine, respectively; 0.9-fold (het EM), cf. hom EM for norfluoxetine; nonsignificant increase in fluoxetine in het EM | Reciprocal changes suggest little overall effect; multiple metabolic pathways; clinical studies lacking | Liu et al. (2001) | |
| Imipramine | Single dose: 1.4-fold; repeated dosing (Cp12 h): 1.7- to 2.4-, 0.6- to 1.0-fold (N.S. in some studies), and 1.8-fold for imipramine, desipramine and imipramine + desipramine, respectively | Multiple metabolic pathways to multiple active metabolites; little evidence for altered effect with CYP2C19 status; concentration-effect relationship ill-defined | Skjelbo et al. (1991); Koyama et al. (1994, 1996b); Morinobu et al. (1997) | |
| Lansoprazole | Single dose: 4.6-fold; 3.7- to 5.6-fold (PM), 1.4- to 1.8-fold (het EM, N.S.), cf. hom EM; repeated dosing: 3.9- to 5.4-fold (PM), 1.7- to 2.4-fold (het EM), cf. hom EM | Treatment failure more likely in homozygous EMs | Very high therapeutic index | Sohn et al. (1997); Furuta et al. (2001c); Ieiri et al. (2001); Sakai et al. (2001); Kim et al. (2002); Shirai et al. (2002) |
| Mephobarbital | Single-dose: 92- and 2.8-fold (PM), 4.4- and 1.3-fold (het EM, N.S.), cf. hom EM for R-mephobarbital and phenobarbital, respectively; no significant difference for S-mephobarbital | This seems to be a world record–more study is needed | Kobayashi et al. (2004) | |
| Moclobemide | Single dose: 2.7-fold; 2.7- to 3.5-fold (PM), 1.3- to 1.7-fold (het EM), cf. hom EM; repeated dosing: 1.6-fold | High therapeutic index; saturable metabolism | Gram et al. (1995); Hoskins et al. (2000); Yu et al. (2001) | |
| Omeprazole | Single dose: 5- to 12-fold; 6- to 20-fold (PM), 2- to 4-fold (het EM), cf. hom EM; repeated dosing: 4.4-fold; 7- to 13-fold (PM), 2- to 5-fold (het EM), cf hom EM | Treatment failure more likely in homozygous EMs | Very high therapeutic index | Andersson et al. (1992); Sohn et al. (1992a); Chang et al. (1995b); Yasuda et al. (1995a); Furuta et al. (1999b); Shirai et al. (2001); Cho et al. (2002) |
| Pantoprazole | Single dose: 6.0-fold | Treatment failure more likely in homozygous EMs | Very high therapeutic index | Tanaka et al. (1997) |
| Proguanil | Single dose: 1.5-fold for proguanil (cycloguanil less than 0.3-fold cf EM); repeated dosing: 0.5-fold for cycloguanil (active metabolite) | Evidence lacking for clinical effects | Helsby et al. (1993); Setiabudy et al. (1995); Thaper et al. (2002); Herrlin et al. (2000) | |
| Rabeprazole | Single dose: 1.8-fold; 3.1- to 4.3-fold (PM); 1.3- to 2.3-fold (het EM, N.S. in all studies), cf hom EM; repeated dosing: 1.9-fold; 3.5- to 5.3-fold (PM); 1.7- to 3.0-fold (het EM, N.S. in all studies), cf. hom EM | Treatment failure more likely in homozygous EMs | Very high therapeutic index | Yasuda et al. (1995a); Horai et al. (2001); Ieiri et al. (2001); Shirai et al. (2001); Lin et al. (2003) |
| Sertraline | Single dose: 1.4-fold | High therapeutic index; concentration-effect relationship ill-defined for the SSRIs | Wang et al. (2001) | |
| Voriconazole | Repeated dosing: 3.8- to 5.8-fold | Clinical implications unclear | Ikeda et al. (2004) |
N.S., not significant