trifluoperazine, hecogenin, and tamoxifen N-glucuronidation appear to be
selective for 1A4. Trifluoperazine may be somewhat problematic due to
nonspecific binding to microsomal proteins and surfaces. UGT1A7–1A10 are
highly homologous (>90%) and have overlapping substrate selectivity for a
number of phenolic substrates, but differ by their tissue distribution. UGT1A9
is expressed highly in liver and kidney, but not in intestine. UGT1A7 is
expressed in the esophagus and gastric epithelium but not in liver. Both
UGT1A8 and UGT1A10 are expressed in intestine, but not in liver. UGT1A8
is also expressed in lung. In liver tissue, propofol and entacapone are selective
substrates for 1A9, but 1A8 and 1A10 can glucuronidate these bulky phenolic
compounds. Entecapone is more selective due to a lowerKmand may be
preferred, but is not widely available. Zidovudine (AZT, azidothymidine)
appears to be fairly selective for UGT2B7, but is also turned over by UGT2B4
with similarKmvalues. Maxipost was the first substrate discovered for the
UGT2B7-catalyzed amide N-glucuronidation with aKmof 13mM (Zhang
et al., 2004). Carbamazepine N-glucuronidation appears to be a UGT2B7
selective substrate, but has a highKm.
Several of these compounds can be employed as selective inhibitors for
screening purposes, such as bilirubin for 1A1, hecogenin for UGT1A4,
serotonin for 1A6, but they should be employed at the proper concentrations
(2–4 thanKm) as they may affect other enzymes at higher concentration.
Unfortunately, selective inhibitory antibodies have not been developed.
Atazanavir appears to be a potent UGT1A1 inhibitor (Zhang et al., 2005).
Fluconazole, a nonsubstrate, appears to be a selective UGT2B7 inhibitor
(Uchaipichat, 2006). Valproic acid and probenecid inhibit multiple UGTs and
may be useful as general inhibitors, but are not selective.
3.1.8 Drug–Drug Interactions and Glucuronidation
A common conception of interactions involving glucuronidation are that they
are not important because of either the availability of multiple enzymes
catalyzing the same reaction or the relatively highKmvalues for many substrates
compared to the P450 enzymes. However, there are several important clinical
interactions that have been delineated. Interactions are likely to occur via
induction by AhR, PXR, CAR, and PPAR activators with individual enzymes
resulting in increased clearance and lowered drug exposure (AUC values).
Inhibitory interactions can occur when glucuronidation is a predominant
metabolic elimination pathway, when the glucuronidation is catalyzed by a
single enzyme and when the therapeutic concentrations of the inhibitor are close
to theKiof the target UGT. These principles have been discussed recently in a
review, but are the same for any inhibitory drug interaction. Drug–drug
interactions involving glucuronidation have been exhaustively reviewed recently
by Kiang et al. (Kiang, 2005) and in a monograph by one of the co-authors
(Remmel, 2000). It is beyond the scope to list all of the drug interactions in this
short review, but some key examples will be discussed.
60 CONJUGATIVE METABOLISM OF DRUGS