Fig. 1.

Drug-drug, drug-gene, and drug-drug-gene interactions. The hepatic extensive (normal) metabolism of small molecule drug A (yellow triangles) requires functional drug-metabolising enzyme Z (DME-Z, blue rectangles) for metabolism to metabolite A (blue circles), as shown in I. In II, DME-Z is inhibited by perpetrator drug B (red triangle) leading to reduced drug A metabolism, and hence a drug-drug interaction (DDI). Similarly in III, the function of DME-Z is reduced by genetic variation (red rectangles) conferring a poor metaboliser (homozygous) genotype, leading to reduced drug A metabolism, and hence a drug-gene interaction (DGI). In IV, a drug-drug-gene interaction (DDGI) is depicted whereby both genetic variation (e.g. a heterozygous intermediate metaboliser genotype) and perpetrator drug B conceivably act together to collectively reduce DME-Z function, strongly attenuating drug A metabolism. In V, drug A is primarily metabolised by DME-Z, but also a second enzyme, DME-Y, (flattened red rectangles) involved to a lesser extent is shown. If perpetrator drug B inhibits DME-Z, less drug A is metabolised by DME-Z and so drug A metabolism is more reliant on DME-Y conversion to metabolite B (green circle). However, if the genotype of DME-Y confers a reduced function (poor metaboliser DME-Y phenotype depicted in V), then the overall metabolism of drug A will be greatly reduced, constituting a DDGI. Similarly, if the functions of both DME-Z and DME-Y were affected by genetic variants, a drug-gene-gene interaction (DGGI) would manifest. The result of all of these interactions is less metabolism and so increased systemic exposure to drug A. These interactions equally apply to perpetrator drug inducers and genetic variation conferring rapid/ultra-rapid metaboliser predicted phenotypes. Similarly, these interactions apply to both deactivating metabolism of active drugs and bioactivation of prodrugs. Beyond enzymes, pharmacokinetic interactions can also be mediated by drug- and/or gene-based alterations to drug transporters