TY - JOUR
T1 - CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP
AU - Huezo-Diaz, Patricia
AU - Perroud, Nader
AU - Spencer, Edgar P
AU - Smith, Rebecca
AU - Sim, Sarah
AU - Virding, Susanne
AU - Uher, Rudolf
AU - Gunasinghe, Cerisse
AU - Gray, Jo
AU - Campbell, Desmond
AU - Hauser, Joanna
AU - Maier, Wolfgang
AU - Marusic, Andrej
AU - Rietschel, Marcella
AU - Perez, Jorge
AU - Giovannini, Caterina
AU - Mors, Ole
AU - Mendlewicz, Julien
AU - McGuffin, Peter
AU - Farmer, Anne E
AU - Ingelman-Sundberg, Magnus
AU - Craig, Ian W
AU - Aitchison, Katherine J
PY - 2012/3
Y1 - 2012/3
N2 - In vitro work shows CYP2C19 and CYP2D6 contribute to the metabolism of escitalopram to its primary metabolite, N-desmethylescitalopram. We report the effect of CYP2C19 and CYP2D6 genotypes on steady state morning concentrations of escitalopram and N-desmethylescitalopram and the ratio of this metabolite to the parent drug in 196 adult patients with depression in GENDEP, a clinical pharmacogenomic trial. Subjects who had one CYP2D6 allele associated with intermediate metabolizer phenotype and one associated with poor metabolizer (i.e. IM/PM genotypic category) had a higher mean logarithm escitalopram concentration than CYP2D6 extensive metabolizers (EMs) (p = 0.004). Older age was also associated with higher concentrations of escitalopram. Covarying for CYP2D6 and age, we found those homozygous for the CYP2C19*17 allele associated with ultrarapid metabolizer (UM) phenotype had a significantly lower mean escitalopram concentration (2-fold, p = 0.0001) and a higher mean metabolic ratio (p = 0.0003) than EMs, while those homozygous for alleles conferring the PM phenotype had a higher mean escitalopram concentration than EMs (1.55-fold, p = 0.008). There was a significant overall association between CYP2C19 genotypic category and escitalopram concentration (p = 0.0003; p = 0.0012 Bonferroni corrected). In conclusion, we have demonstrated an association between CYP2C19 genotype, including the CYP2C19*17 allele, and steady state escitalopram concentration.
AB - In vitro work shows CYP2C19 and CYP2D6 contribute to the metabolism of escitalopram to its primary metabolite, N-desmethylescitalopram. We report the effect of CYP2C19 and CYP2D6 genotypes on steady state morning concentrations of escitalopram and N-desmethylescitalopram and the ratio of this metabolite to the parent drug in 196 adult patients with depression in GENDEP, a clinical pharmacogenomic trial. Subjects who had one CYP2D6 allele associated with intermediate metabolizer phenotype and one associated with poor metabolizer (i.e. IM/PM genotypic category) had a higher mean logarithm escitalopram concentration than CYP2D6 extensive metabolizers (EMs) (p = 0.004). Older age was also associated with higher concentrations of escitalopram. Covarying for CYP2D6 and age, we found those homozygous for the CYP2C19*17 allele associated with ultrarapid metabolizer (UM) phenotype had a significantly lower mean escitalopram concentration (2-fold, p = 0.0001) and a higher mean metabolic ratio (p = 0.0003) than EMs, while those homozygous for alleles conferring the PM phenotype had a higher mean escitalopram concentration than EMs (1.55-fold, p = 0.008). There was a significant overall association between CYP2C19 genotypic category and escitalopram concentration (p = 0.0003; p = 0.0012 Bonferroni corrected). In conclusion, we have demonstrated an association between CYP2C19 genotype, including the CYP2C19*17 allele, and steady state escitalopram concentration.
KW - Adult
KW - Aged
KW - Antidepressive Agents/blood
KW - Aryl Hydrocarbon Hydroxylases/genetics
KW - Biotransformation
KW - Citalopram/analogs & derivatives
KW - Cytochrome P-450 CYP2C19
KW - Cytochrome P-450 CYP2D6/genetics
KW - Depressive Disorder, Major/blood
KW - Diagnostic and Statistical Manual of Mental Disorders
KW - European Continental Ancestry Group
KW - Female
KW - Genetic Association Studies
KW - Genotype
KW - Humans
KW - Male
KW - Middle Aged
KW - Polymorphism, Genetic
KW - Serotonin Uptake Inhibitors/blood
KW - Young Adult
U2 - 10.1177/0269881111414451
DO - 10.1177/0269881111414451
M3 - Article
C2 - 21926427
SN - 0269-8811
VL - 26
SP - 398
EP - 407
JO - Journal of psychopharmacology (Oxford, England)
JF - Journal of psychopharmacology (Oxford, England)
IS - 3
ER -
