Distinct Associations of Age and CYP2D6 Genotype With Parent Venlafaxine Exposure and O-Demethylation in Japanese Psychiatric Patients.
- 1Department of Psychiatry, Dokkyo Medical University School of Medicine, Tochigi, Japan.
Abstract
Venlafaxine (VEN) is converted to O-desmethylvenlafaxine (ODV) mainly through CYP2D6-mediated O-demethylation. However, age-related clinical factors may also influence VEN exposure in routine practice. We examined whether age and CYP2D6 genotype show different associations with parent-drug exposure and metabolic conversion. This retrospective therapeutic drug monitoring analysis included 78 Japanese psychiatric patients with available plasma VEN and ODV concentrations and CYP2D6 genotype data. Two prespecified outcomes were analyzed without body-weight correction: VEN concentration divided by daily dose (VEN/dose) and the ODV/VEN ratio. CYP2D6*10 and *5 were coded as reduced- and no-function alleles, respectively. Log-transformed outcomes were analyzed using regression models including age and CYP2D6 reduced/no-function allele count. Nineteen patients (24.4%) were aged 65 years or older. Age was correlated with VEN/dose (Spearman rho = 0.295, p = 0.0086), and older patients had higher VEN/dose than younger patients (median, 0.522 vs. 0.192 [ng/mL]/[mg/day], p = 0.0127). In regression analysis, the incremental R2 for age was numerically larger than that for CYP2D6 allele count for VEN/dose (incremental R2, 0.058 vs. 0.026). Conversely, the ODV/VEN ratio was strongly associated with CYP2D6 allele count (standardized beta = -0.391, p < 0.001; incremental R2 = 0.145) but not with age. Age-by-genotype interactions were not significant for either outcome. Age appeared to be more closely related to dose-corrected parent VEN exposure, whereas CYP2D6 genotype predominantly determined the ODV/VEN metabolic ratio. The relative contribution of age should be interpreted descriptively because no formal comparison of effect sizes was performed. Separating exposure and metabolic-ratio outcomes may clarify how geriatric and pharmacogenetic factors contribute to VEN disposition.
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BibTeX
@article{ishihara2026distinct,
title = {{Distinct Associations of Age and CYP2D6 Genotype With Parent Venlafaxine Exposure and O-Demethylation in Japanese Psychiatric Patients.}},
author = {Yugo Ishihara and Taro Sasaki and Tomohiro Asahi and Yujin Ono and Tomomi Sugisaki and Rina Hiramatsu and Yasushi Kawamata and Norio Sugawara and Norio Yasui-Furukori},
journal = {Neuropsychopharmacology reports},
year = {2026},
month = oct,
doi = {10.1002/npr2.70175},
url = {https://europepmc.org/article/MED/42956830},
note = {CC BY},
}
RIS
TY - JOUR
TI - Distinct Associations of Age and CYP2D6 Genotype With Parent Venlafaxine Exposure and O-Demethylation in Japanese Psychiatric Patients.
AU - Yugo Ishihara
AU - Taro Sasaki
AU - Tomohiro Asahi
AU - Yujin Ono
AU - Tomomi Sugisaki
AU - Rina Hiramatsu
AU - Yasushi Kawamata
AU - Norio Sugawara
AU - Norio Yasui-Furukori
PY - 2026
DA - 2026/10/29
JO - Neuropsychopharmacology reports
DO - 10.1002/npr2.70175
UR - https://europepmc.org/article/MED/42956830
AB - Venlafaxine (VEN) is converted to O-desmethylvenlafaxine (ODV) mainly through CYP2D6-mediated O-demethylation. However, age-related clinical factors may also influence VEN exposure in routine practice. We examined whether age and CYP2D6 genotype show different associations with parent-drug exposure and metabolic conversion. This retrospective therapeutic drug monitoring analysis included 78 Japanese psychiatric patients with available plasma VEN and ODV concentrations and CYP2D6 genotype data. Two prespecified outcomes were analyzed without body-weight correction: VEN concentration divided by daily dose (VEN/dose) and the ODV/VEN ratio. CYP2D6*10 and *5 were coded as reduced- and no-function alleles, respectively. Log-transformed outcomes were analyzed using regression models including age and CYP2D6 reduced/no-function allele count. Nineteen patients (24.4%) were aged 65 years or older. Age was correlated with VEN/dose (Spearman rho = 0.295, p = 0.0086), and older patients had higher VEN/dose than younger patients (median, 0.522 vs. 0.192 [ng/mL]/[mg/day], p = 0.0127). In regression analysis, the incremental R2 for age was numerically larger than that for CYP2D6 allele count for VEN/dose (incremental R2, 0.058 vs. 0.026). Conversely, the ODV/VEN ratio was strongly associated with CYP2D6 allele count (standardized beta = -0.391, p < 0.001; incremental R2 = 0.145) but not with age. Age-by-genotype interactions were not significant for either outcome. Age appeared to be more closely related to dose-corrected parent VEN exposure, whereas CYP2D6 genotype predominantly determined the ODV/VEN metabolic ratio. The relative contribution of age should be interpreted descriptively because no formal comparison of effect sizes was performed. Separating exposure and metabolic-ratio outcomes may clarify how geriatric and pharmacogenetic factors contribute to VEN disposition.
SN - 2574-173X
ER -