Drug-drug-gene interactions and adverse drug reactions

Abstract

The economic and health burden caused by adverse drug reactions has increased dramatically in the last few years. This is likely to be mediated by increasing polypharmacy, which increases the likelihood for drug-drug interactions. Tools utilized by healthcare practitioners to flag potential adverse drug reactions secondary to drug-drug interactions ignore individual genetic variation, which has the potential to markedly alter the severity of these interactions. To date there have been limited published studies on impact of genetic variation on drug-drug interactions. In this review, we establish a detailed classification for pharmacokinetic drug-drug-gene interactions, and give examples from the literature that support this approach. The increasing availability of real-world drug outcome data linked to genetic bioresources is likely to enable the discovery of previously unrecognized, clinically important drug-drug-gene interactions.

Fig. 1

The predicted active drug/active metabolites of prodrugs plasma levels and biliary excretion changes without or with the presence of inhibitors or LOF variants or both on metabolizing enzymes. The predicted active drug/active metabolites of prodrugs plasma levels and biliary excretion changes without (a-1/a-2) or with the presence of inhibitors or LOF variants (b-1/b-2) or both (c-1/c-2) on metabolizing enzymes. a-1/a-2 represent the normal scenario with no interacting drug or genetic variant. In b-1/b-2 either an inhibitory drug or loss-of-function variant (LOF) in the metabolizing enzyme, results in reduced metabolism to inactive metabolites, and increased (b-1)/decreased (b-2) active drug in the systemic circulation. In c-1/c-2 the presence of inhibitory drug and the LOF genetic variant combine to produce greater increase (c-1)/decrease (c-2) in the systemic concentration of active drug

Fig. 2

The predicted active drug/active metabolites of prodrugs plasma levels and biliary excretion changes with out or with the presence of inducers or GOF variants or both on metabolizing enzymes. The predicted active drug/active metabolites of prodrugs plasma levels and biliary excretion changes without (a-1/a-2) or with the presence of inducers or GOF variants (b-1/b-2) or both (c-1/c-2) on metabolizing enzymes. a-1/a-2 represent the normal scenario with no interacting drug or genetic variant. In b-1/b-2 either an inducer drug or gain-of-function variant (GOF) in the metabolizing enzyme, results in increased metabolism to inactive metabolites, and decreased (b-1)/increased (b-2) active drug in the systemic circulation. In c-1/c-2 the presence of inducer drug and the GOF genetic variant combine to produce greater decrease(c-1)/increase(c-2) in the systemic concentration of active drug

Fig. 3

Different scenarios of phenoconversion interactions where genetic effects may be reversed or shifted in the opposite direction. a Represents the normal scenario with no interacting drug or genetic variant. In b the effect of loss-of-function variant (LOF) or gain-of-function variant (GOF) is reversed with the presence of a moderate inducer drug or a moderate inhibitor drug respectively and results in a clinical outcome similar to the normal situation (a). In c the presence of a strong inducer drug has temporarily shifted a poor metabolism status into a rapid metabolism status and results in decreased active drug in the systemic circulation. In d the presence of a strong inhibitor drug has temporarily shifted a rapid metabolism status into a poor metabolism status and results in increased active drug in the systemic circulation

Fig. 4

Drug transporters as classified into three categories according to the similarity of the transport directions in different tissue types. Numbers from to  = order of oral drug movement through different tissue types. Nonoral drug formulations bypass the effect of intestinal transporters. / = increased/decreased substrate drug plasma level is predicted as a result of impairment of this transporter due to LOF variants or inhibitors. The reverse is predicted with GOF variants or inducers. The presence of the two factors (i.e. LOF variant + an inhibitor or GOF variant + an inducer) is predicted to double the clinical impact with neutralizing or shifting the clinical effect when the preparator drug and genetic effect are opposed (phenoconversion interactions).  = Apical membrane.  = Basolateral membrane