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      To evaluate a compound’s potential to be a victim of DDI, it is necessary to identify the specific enzymes involved in its metabolism. A common experimental approach to reaction phenotyping (Harper and Brassil, 2008; Zhang et al., 2009) is the use of cDNA‐expressed recombinant enzyme systems, in which the test compound is incubated with a panel of individually expressed human recombinant enzymes. A typical panel of CYP enzymes includes CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, and 3A5. Using the known CYP abundances60, 61, the percentage contribution of individual CYPs to the overall oxidative metabolism of a drug candidate (fm,CYP ) can be estimated:

      (2.2)equation

      In vitro data are associated with uncertainty due to knowledge gaps in system parameters or scalars. The data may also vary considerably between laboratories due to differences in donors and assays. When an NCE is a perpetrator of drug interaction, the unbound drug concentration at the site of interaction is uncertain, if the compound is a transporter substrate and/or highly bound to plasma proteins. This is especially true for efflux transporter inhibition or for CYP induction, where the driving concentrations are intracellular drug concentrations. The uncertainty in driving concentrations are even higher when these processes occur in the gut. In early development, the therapeutic dose of the perpetrator NCE drug is not identified and can add to the uncertainty in the DDI risk assessment. Sources of uncertainty are listed below:

      NCE as victim

       Contribution of gut for CYP3A and UGT substrates, fg;

       Fraction metabolized, fm

       fm,CYP

      NCE as perpetrator

       In vitro interaction parameters (Ki, kinact, KI, EC50 )

       In vivo relevance of transporters in determining the intracellular concentrations of inhibitors that are substrates for uptake and/or efflux transporters

       Protein binding of highly plasma‐bound drugs

       Final dose

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      4 Backman, J.T. et al. (2005). Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites. Clinical Pharmacology and Therapeutics 78 (2): 154–167. https://doi.org/10.1016/j.clpt.2005.04.007.

      5 Bendayan, R. et al. (1990). Effect

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