ABSTRACT:The IC 50 values of 14 drugs were determined in recombinantly expressed CYP2C9 (rCYP2C9) and human hepatocytes and the data used to simulate clinical area under the plasma concentration-time curve (AUC) changes upon coadministration with prototypic CYP2C9 substrates. There was an excellent correlation between IC 50 Up to 2.8% of hospital admissions may be a consequence of drug-drug interactions (DDIs) (Jankel and Fitterman, 1993). Although metabolic DDIs have been reported for several enzyme families, it is clearly recognized that inhibition of cytochrome P450 (P450)-dependent metabolism is one of the more prevalent sources of such reactions and may have a serious outcome (Bertz and Granneman, 1997). Experiences with terfenadine (Honig et al., 1993), cisapride (Ahmad and Wolfe, 1995), and mibefradil (Krayenbuhl et al., 1999) have highlighted the importance of understanding the enzymology of drug metabolism to assess its impact on pharmacodynamics and toxicology.An assessment of the potential of a new chemical entity to cause a DDI via inhibition of P450 metabolism is important early in the drug discovery process. Thus, a battery of automated in vitro screens to determine the degree of P450 inhibition are now routinely used in drug metabolism and pharmacokinetics departments across the pharmaceutical industry. Such screens are used both for the evaluation and optimization of potential candidate drugs and for prioritizing and designing suitable in vitro and clinical interaction studies in the drug development phase. The ability to predict in vivo DDIs from human in vitro assays would represent a major advance in drug discovery.Approaches to predicting P450-mediated DDI potential have traditionally involved the use of human liver microsomes, although more recently, the use of recombinant cytochrome P450s (rP450s) has become widespread. More often than not, these assays focus on the five major drug-metabolizing P450s: CYP1A2, 2C9, 2C19, 2D6, and 3A4. Human hepatocytes in primary culture provide the closest in vitro model to human liver and have been excellent tools for elucidating the metabolic profile of drugs, for predicting hepatic metabolic clearance (McGinnity et al., 2004;Riley et al., 2005), for studying hepatotoxicity of drugs (Gomez-Lechon et al., 2001), and for the mechanistic understanding of DDIs mediated via P450 induction (LeCluyse et al., 2000). There are sporadic reports of the use of human hepatocytes to characterize P450 inhibition Cohen et al., 2000;Oleson et al., 2004;Zhao et al., 2005), but it is notable that investigations of inhibitory mechanisms remain under-represented compared with studies on metabolism and induction. This is likely due to the relative accessibility of recombinant P450s and their overall applicability in predicting clinically relevant DDIs. Availability of
A generalized, quantitative model is proposed for the inhibition of the major drug metabolizing enzyme, CYP3A4. This model indicates the importance of lipophilicity and rationalizes increased potency arising through additional interactions with the heme iron. These general relationships were shown to be applicable to a selection of compounds of interest to several early research projects.
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