UGT Reaction Phenotyping

FIGURE 15.1 Three independent approaches for definitive cytochrome P450 phenotyping that can also be applied to UGT phenotyping. 

Other major obstacles to quantitative extrapolation of in vitro data to predict clearance of UGT substrates in humans include knowledge of relative 

A recent example of UGT reaction phenotyping is that for gemcabene, a Pfizer compound indicated for treatment of dyslipidemia, and cleared primarily via a single glucuronide in humans (Bauman et al., 2005). The strategy employed for UGT reaction phenotyping compound is outlined in Fig. 15.2. Although human liver microsomes were assayed in this example, the same experimental approach could also be used for human intestinal microsomes. A brief summary of the approach and key data follows. 

The approaches described above (Bauman et al., 2005) present a resourceintensive description of definitive UGT reaction phenotyping. Depending on need, one or more of the described steps may be omitted. The area primed for the greatest advance in the near future is the identification of selective glucuronidation inhibitors. Note that competitive substrates for individual enzymes are not necessarily selective inhibitors of those enzymes, since compounds do not need to be substrates of a UGT enzyme to be an inhibitor of that enzyme (Williams et al., 2002a). Recent advances have also been made in in silica predictions (Sorich et al., 2002). This promising area should be monitored for significant advances. 

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