Question

Which of the 3 main inhibitory mechanisms (complete inhibition, noncompetitive inhibition, irreversible inhibition) has the greatest potential for ADRs (adverse drug reactions)?

Answer 1

Human drug metabolising enzymes can be induced or inhibited by drugs, foodstuffs, and
alcohol, which can predispose to toxicity from both endogenous and exogenous substrates. For
endogenous substrates, enzyme inhibition can lead to a deficiency of an essential metabolite
or accumulation of an otherwise non-toxic compound. Enzyme induction by increasing
metabolism of endogenous compounds can lead to a deficiency state, e.g. vitamin D deficiency
with phenytoin. With drugs, perturbation of enzyme activity can lead to both type A and type
B adverse drug reactions (ADRs) depending on whether phase I or phase II pathways are
affected. Thus type A ADRs can result from inhibition or induction of phase I pathways, the
toxicity being due to the parent drug or active metabolite, respectively. Type B ADRs result
form induction of phase I, or inhibition of phase II pathways, with a resultant imbalance
between bioactivation and detoxication. Knowledge of drug effects on metabolic pathways is
important so that their potential to cause toxicity can be anticipated. In the long-term, it is
important to develop "cleaner" compounds so that the problem of enzyme inhibition and
enzyme induction can be eliminated, and together with it, the potential of such drugs to cause
ADRs