Understanding of genetic influence on pharmacokinetic variability for drugs
primarily cleared by glucuronidation has advanced more rapidly in recent years,
and convincing evidence of functionally relevant polymorphisms exists only for
theUGT1A1gene (Miners et al., 2002). The UGT1A1 substrate SN-38 is an
active cytotoxic metabolite of irinotecan (Camptosar), indicated for treatment of
colon cancer, and UGT1A1 genotype may therefore offer a useful safety
biomarker for lower therapeutic index drugs that are primarily cleared by
UGT1A1 (Pharmacia and Upjohn, 2004). Drugs thought to be primarily cleared
by UGT1A4 include lamotrigine (Williams et al., 2004), and drugs cleared
primarily by UGT2B7 include zidovudine (Williams et al., 2004) and gemcabene
(Bauman et al., 2005).
As detailed below, selective chemical inhibition, recombinant UGT
enzymes, and correlation analysis are the three independent approaches used
for definitive cytochrome P450 phenotyping (Bjornsson et al., 2003) that can
also be applied to UGT phenotyping (Fig. 15.1). The cytochrome P450 field is
relatively advanced compared to that for UGT reaction phenotyping in that
potent and selective chemical inhibitors in addition to probe substrates are well
characterized for the major drug metabolizing members of the cytochrome
P450 family only (Williams et al., 2005). Flavonoids such as hexamethoxy-
flavone (Williams et al., 2004) and tangeretin (Williams et al., 2002a) have been
identified as potent inhibitors of UGT1A1, but selectivity is an issue in that
these compounds also potently inhibit UGT1A6 and UGT1A9, and possibly
other UGT1A enzymes (Goosen et al., 2003).UGT2B7 enzyme activity,
however, is not inhibited by flavonoids (Williams et al., 2004). As with
cytochrome P450 enzymes, inhibition of UGT enzymes may be substrate
selective (Rios and Tephly, 2002). Thus, although flurbiprofen (Bauman et al.,
2005) and fluconazole (Uchaipichat et al., forthcoming) demonstrate selectivity
in inhibition of UGT2B7-catalyzed fluconazole and gemcabene glucuronida-
tion respectively, it is not necessarily the case that they are suitable for
inhibition of all UGT2B7-catalyzed reactions. Until knowledge and under-
standing of UGT inhibition sufficiently develops, it may therefore be necessary
to characterize potency and selectivity of inhibition for glucuronidated drugs
using panels of recombinant enzymes where enzyme-selective substrates are
absent, before human liver microsomes.
Other major obstacles to quantitative extrapolation of in vitro data to
predict clearance of UGT substrates in humans include knowledge of relative
FIGURE 15.1 Three independent approaches for definitive cytochrome P450
phenotyping that can also be applied to UGT phenotyping.
CONJUGATION PHENOTYPING 485