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