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Vol. 30, Issue 6, 694-700, June 2002
University of North Carolina, Curriculum of Toxicology, Chapel
Hill, North Carolina (D.C.K.); and Global Drug Metabolism, Pharmacia
Corporation, Kalamazoo, Michigan (P.W.F., J.C.S.)
Raloxifene, a selective estrogen receptor modulator used for the
treatment of osteoporosis, undergoes extensive conjugation to the
6-
- and 4'--glucuronides in vivo. This paper investigated raloxifene glucuronidation by human liver and intestinal microsomes and
identified the responsible UDP-glucuronosyltransferases (UGTs). UGT1A1
and 1A8 were found to catalyze the formation of both the 6-- and
4'--glucuronides, whereas UGT1A10 formed only the
4'--glucuronide. Expressed UGT1A8 catalyzed 6--glucuronidation
with an apparent Km of 7.9 µM and a
Vmax of 0.61 nmol/min/mg of protein and
4'--glucuronidation with an apparent Km
of 59 µM and a Vmax of 2.0 nmol/min/mg.
Kinetic parameters for raloxifene glucuronidation by expressed UGT1A1 could not be determined due to limited substrate solubility. Based on
rates of raloxifene glucuronidation and known extrahepatic expression,
UGT1A8 and 1A10 appear to be primary contributors to raloxifene
glucuronidation in human jejunum microsomes. For human liver
microsomes, the variability of 6-- and 4'--glucuronide formation
was 3- and 4-fold, respectively. Correlation analyses revealed that
UGT1A1 was responsible for 6-- but not 4'--glucuronidation in
liver. Treatment of expressed UGTs with alamethicin resulted in minor
increases in enzyme activity, whereas in human intestinal microsomes,
maximal increases of 8-fold for the 6-glucuronide and 9-fold for the
4'-glucuronide were observed. Intrinsic clearance values in intestinal
microsomes were 17 µl/min/mg for the 6-glucuronide and 95 µl/min/mg
for the 4'-isomer. The corresponding values for liver microsomes were
significantly lower, indicating that intestinal glucuronidation may be
a significant contributor to the presystemic clearance of raloxifene in vivo.
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