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

Area of Science:

• Pharmacogenetics
• Drug Metabolism
• Clinical Pharmacology

Background:

• Pharmacogenetics (PGx) predicts drug response using genetic variations in drug-metabolizing enzymes.
• Observed drug metabolism can deviate from genotype-predicted status due to external factors, a phenomenon termed phenoconversion.
• Understanding phenoconversion is crucial as PGx testing integrates into clinical practice.

Purpose of the Study:

• To categorize reported contributors of phenoconversion affecting CYP2D6, CYP2C19, and CYP3A4 metabolism.
• To review literature on factors influencing the discrepancy between genotype-predicted and actual drug metabolism.

Main Methods:

• A scoping review of literature was performed using multiple databases (Ovid MEDLINE®, Embase, EBM Reviews, Web of Science).
• Studies were screened for inclusion criteria, and data were extracted on factors associated with metabolic activity inconsistent with genotype-predicted phenotypes.
• 43 studies were included from an initial 6008 records.

Main Results:

• Identified phenoconversion contributors included pharmacological (drug-drug, drug-drug-gene interactions), clinical (inflammation), physiological/demographic (pregnancy, age), and environmental (smoking) factors.
• Pharmacological factors were most frequently reported.
• Environmental and demographic influences on phenoconversion were less characterized.

Conclusions:

• Phenoconversion is a multifactorial phenomenon influenced by a range of external factors.
• Further research is needed to fully characterize these influences and integrate phenoconversion into PGx-informed clinical decision-making.
• Accurate interpretation of PGx testing requires consideration of factors beyond genetics.