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- W4309355535 endingPage "526" @default.
- W4309355535 startingPage "465" @default.
- W4309355535 abstract "Understanding clinical drug–drug interaction (DDI) risks which are a result of inhibition of major human cytochrome P450 enzymes is a critical activity associated with drug development. In addition to interactions based upon competitive or reversible inhibition, there is an increasing number of clinical DDIs observed which arise via mechanism-based inactivation. These types of interactions are confounding as the inactivated P450 proteins are catalytically incompetent and must be resynthesized in order to achieve normal protein levels. As a consequence, mechanism-based inactivation of P450s represents a marked safety concern compared to reversible inhibition because of the increased propensity for pharmacokinetic interactions as the sustained duration of low enzyme levels exists even after the discontinuation of the inhibitor. In addition to potent P450 inhibition, these types of inhibitors pose an additional risk drug toxicity as the mechanism of time-dependency typically involves the formation of reactive metabolites, which if they escape the P450 active site may react with a variety of endogenous macromolecules. The aim of the current chapter is to describe key experimental activities which may help underwrite the nature and magnitude of clinical DDIs risks associated with a novel drug candidate." @default.
- W4309355535 created "2022-11-26" @default.
- W4309355535 creator A5047250345 @default.
- W4309355535 creator A5057350210 @default.
- W4309355535 date "2022-11-18" @default.
- W4309355535 modified "2023-10-16" @default.
- W4309355535 title "Characterization of Cytochrome <scp>P450</scp> Mechanism Based Inhibition" @default.
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