Factors Influencing Phenoconversion in CYP-Mediated Drug Metabolism: A Scoping Review

Pharmacogenetics (PGx) aims to optimize drug therapy by predicting medication response based on genetic variation in drug-metabolizing enzymes. However, observed drug metabolism may differ from genotype-predicted metabolizer status given external or acquired influences. This phenomenon is known as phenoconversion. As PGx testing becomes increasingly integrated into clinical care, understanding the contributing factors of phenoconversion is important for interpreting test results and guiding treatment. This scoping review aimed to categorize reported contributors of phenoconversion affecting CYP2D6, CYP2C19, and CYP3A4 metabolism. A structured literature search was conducted across Ovid MEDLINE^®, Embase Classic + Embase, EBM Reviews, and Clarivate Web of Science. Records were screened using predefined inclusion and exclusion criteria, and data were extracted from eligible studies describing factors associated with metabolic activity inconsistent with genotype-predicted phenotypes. From 6008 records identified, 43 studies met the inclusion criteria. Reported contributors clustered into pharmacological factors, including drug-drug and drug-drug-gene interactions, clinical factors such as inflammation, physiological and demographic factors including pregnancy and age-related changes, and environmental influences such as smoking. Pharmacological contributors were most frequently studied, whereas environmental and demographic influences were less well characterized. These findings highlight the multifactorial nature of phenoconversion and underscore the need for further investigations to support phenoconversion integration into PGx-informed clinical decision-making.