New Compounds as Potential DDI Perpetrators

Prediction of DDI from in vitro inactivation data has also been accomplished. However, unlike the aforementioned simple cutoff that can be applied to inhibition data, no such simple cutoff criterion has been well established for mechanism-based inactivation kinetic parameters. Ratios of k act/kdeg and [ ] vivolKi have been shown to be related to the magnitude of DDI [50]. The early screens previously discussed rely upon abbreviated approaches to identify mechanism-based inactivation as an issue rather than provide quantitative data for predictions of DDI. 

To make quantitative predictions of DDI for the new compound as perpetrator, a reliable estimate of a relevant in vivo concentration is needed. What is tmly needed is knowledge of the concentration of the inhibitor available to bind to the enzyme. For liver, if the well accepted free-dmg hypothesis (which underwrites fundamental drug action principles in pharmacology) is applied for DDI, then the use of a free intracellular liver concentration is needed. For inhibitors that are permeable through membranes, the free concentration in the portal vein should serve as the closest proxy for free intracellular concentration in the liver. Diminished permeability as well as active uptake and efflux from liver cells can confound this relationship. Nevertheless, use of estimates of unbound portal vein concentrations (which can be estimated from 

Drug CYP Pharmacological target CYP potency (pM) Target potency (pM) Potency ratio DDI magnitude 

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