The quantitative impact of metabolism-inhibiting drugs on the occurrence of adverse drug reactions — A backward selection approach

Cumulative burden score of metabolic pathway inhibition (including *CYP2D6*, *CYP2C19*, *CYP3A4*) to predict falls and hemorrhages linked to inhibitory comedications

Using a prospective multicenter cohort of adverse drug reactions admitted to emergency departments (ADRED study), this work builds a cumulative metabolic pathway inhibition burden score to identify pathways whose inhibition increases adverse-event risk. For falls, the CYP2D6, OCT2 and carboxylesterase 1 pathways are identified; for hemorrhages, CYP2C19, CYP3A4, MRP4, OAT2, OATP1B1 and carboxylesterase 1. The approach highlights that cumulative pathway inhibition burden can contribute to adverse events. The authors stress the need for validation in a second dataset.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The concept of a cumulative inhibition burden integrating several pathways is conceptually appealing and aligns with the logic of comedication-driven phenoconversion. The backward selection method remains exploratory, however, and requires external validation, as the authors acknowledge. Useful for raising awareness of inhibitory polypharmacy, but not yet translatable into a prescribing tool.