TDI can be divided into a number of mechanistic categories including irreversible (covalent) modification of the enzyme (mechanism based inactivation), quasi-irreversible (metabolite-intermediate complex), reversible (metabolite is more potent inhibitor than parent), etc. TDI is manifested by difference in IC 50 values measured under two different conditions: pre-incubation of a test article with an enzyme and a cofactor NADPH, which produces metabolites, and pre-incubation without NADPH. Their inhibitory potency increases with incubation time. CYP450 mediated transformation of these compounds results in metabolites which act as reversible inhibitors or modify chemically enzyme (e.g. In addition to competitive inhibition of CYP450, some compounds display time dependent inhibition. IC 50 shift assay is a current standard approach for preliminary assessment of TDI. Background: Time dependent inhibition (TDI) gains an increasingly greater attention as a predictor of the drug-drug interaction potential of clinical candidates.
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