Estimating metabolic pathway overlap in precision oncology: integrating pharmacogenetics and polypharmacy
- 1Internal Medicine IX - Department of Clinical Pharmacology and Pharmacoepidemiology, Medical Faculty Heidelberg, Heidelberg University Hospital, Heidelberg University
- 2Department of Internal Medicine I, Ulm University Hospital
Abstract
Introduction: While metabolic pathway overlap is frequent in polypharmacy patients, the modification of genotype-predicted metabolic phenotypes by other substrates is not well established yet, and its relevance for pharmacogenetic implementation in gastrointestinal oncology has not been systematically assessed. We aimed to quantify the overlap between pharmacogenetically relevant treatment pathways and concomitant medications in routine gastrointestinal cancer care.
Methods: Guideline-recommended drugs for gastrointestinal malignancies were evaluated regarding their dependence on pharmacogenetically relevant enzymes. In parallel, real-world co-medication profiles were analyzed to assess the prevalence of inhibitors and inducers of these identified enzymes, as well as the substrate-mediated pathway sharing.
Results: Only a minority of systemic anticancer drugs recommended in treatment guidelines were directly affected by established pharmacogenetic polymorphisms, mainly involving CYP2D6, CYP2C19, CYP2C9, and related pathways. In contrast, co-medication profiles with medications sharing common metabolic pathways were highly prevalent whereas recognized moderate or strong inhibitors were much less frequent (<10%).
Conclusion: Although relatively few anticancer therapies are directly affected by actionable pharmacogenetic variants, the potential for metabolic pathway overlap may increase the clinical relevance of pharmacogenetics in gastrointestinal oncology. By systematically quantifying the coexistence of inhibiting co-medication as well as substrate-mediated pathway sharing, this study provides descriptive explorative estimates of the metabolic pathway-overlap burden. These findings suggest that pharmacogenetic implementation strategies should consider both genotype and medication-related pathway overlap to better inform estimates of drug exposure and support precision oncology.
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BibTeX
@article{stingl2026estimating,
title = {{Estimating metabolic pathway overlap in precision oncology: integrating pharmacogenetics and polypharmacy}},
author = {Julia C. Stingl and Dominik M. Krzoska and Jule A. Neiss and Jakob Sommer and Thomas Ettrich and Hanna M. Seidling and Thomas Seufferlein},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1947359},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1947359/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Estimating metabolic pathway overlap in precision oncology: integrating pharmacogenetics and polypharmacy
AU - Julia C. Stingl
AU - Dominik M. Krzoska
AU - Jule A. Neiss
AU - Jakob Sommer
AU - Thomas Ettrich
AU - Hanna M. Seidling
AU - Thomas Seufferlein
PY - 2026
DA - 2026/10/26
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1947359
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1947359/full
AB - Introduction: While metabolic pathway overlap is frequent in polypharmacy patients, the modification of genotype-predicted metabolic phenotypes by other substrates is not well established yet, and its relevance for pharmacogenetic implementation in gastrointestinal oncology has not been systematically assessed. We aimed to quantify the overlap between pharmacogenetically relevant treatment pathways and concomitant medications in routine gastrointestinal cancer care. Methods: Guideline-recommended drugs for gastrointestinal malignancies were evaluated regarding their dependence on pharmacogenetically relevant enzymes. In parallel, real-world co-medication profiles were analyzed to assess the prevalence of inhibitors and inducers of these identified enzymes, as well as the substrate-mediated pathway sharing. Results: Only a minority of systemic anticancer drugs recommended in treatment guidelines were directly affected by established pharmacogenetic polymorphisms, mainly involving CYP2D6, CYP2C19, CYP2C9, and related pathways. In contrast, co-medication profiles with medications sharing common metabolic pathways were highly prevalent whereas recognized moderate or strong inhibitors were much less frequent (<10%). Conclusion: Although relatively few anticancer therapies are directly affected by actionable pharmacogenetic variants, the potential for metabolic pathway overlap may increase the clinical relevance of pharmacogenetics in gastrointestinal oncology. By systematically quantifying the coexistence of inhibiting co-medication as well as substrate-mediated pathway sharing, this study provides descriptive explorative estimates of the metabolic pathway-overlap burden. These findings suggest that pharmacogenetic implementation strategies should consider both genotype and medication-related pathway overlap to better inform estimates of drug exposure and support precision oncology.
SN - 1663-9812
ER -