Fig. 1.

Schematic illustration of the drug-protein interactions necessary for drug-drug interaction (DDI)-induced adverse drug reactions (ADRs). Drugs i and j interact with proteins α, β, γ, δ, ε, and ζ to induce both therapeutic effects as well as adverse effects Ψ, Ω, and Φ. In Case I, simultaneous drug interaction with both proteins α and β is necessary for a DDI to induce ADR Φ. Because drug i interacts with α but not β and drug j interacts with β but not α, no DDI occurs when the two drugs are administered individually. However, when the two drugs are co-administered, the requirement of simultaneous drug interaction with both α and β, and hence the condition for DDI-induced ADR Φ, are satisfied. In Case II, an existing adverse effect Ω caused by drug j is enhanced by drug i interacting with α, aggravating the adverse effect to a degree that is not possible by drug j alone