title: Assessment of the time-dependent inhibition (TDI) potential of test compounds with human liver microsomes by IC50 shift method using a nondilution approach.
abstract: Time-dependent inhibition (TDI) of hepatic cytochrome P450 (CYP) enzymes is increasingly implicated in the majority of clinically relevant drug-drug interactions (DDIs). A time-dependent inhibitor or its reactive metabolite irreversibly inactivates CYP enzymes, thereby inhibiting the metabolism of other drugs. As the majority of marketed drugs are metabolized by CYP enzymes, their inhibition has important clinical consequences, such as in decreasing the metabolic clearance of a co-administered drug (victim drug). This could be life threatening, as such an effect narrows the therapeutic index for drugs such as warfarin and other potentially toxic agents. Therefore, it is essential to examine new chemical entities for their potential to cause TDI to minimize adverse drug reactions during human studies and use. This unit presents an in vitro procedure utilizing a nondilution method in human liver microsomes for determining the TDI potential of test compounds.
authors.affiliation: NoAb BioDiscoveries, Mississauga, Ontario, Canada.
authors.forename: Lian
authors.initials: L
authors.lastname: de Ron
authors.forename: Ganesh
authors.initials: G
authors.lastname: Rajaraman
mesh_terms: D004336:Drug Antagonism; D004347:Drug Interactions; D057075:Enzyme Assays / Q000379:methods; D006801:Humans; D007201:Indicator Dilution Techniques; D007202:Indicators and Reagents; D020128:Inhibitory Concentration 50; D008099:Liver / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D013997:Time Factors
chemical_list: D007202:Indicators and Reagents