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Vol. 30, Issue 6, 636-642, June 2002
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences,
Kanazawa University, Kanazawa, Japan (M.N., E.T., T.Ko., T.Y.); and
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan
(N.O., T.Ku.)
A method for the direct determination of imipramine
N-glucuronidation in human liver microsomes by
high-performance liquid chromatography with UV detection was developed.
Imipramine was incubated with human liver microsomes and UDP-glucuronic
acid. The Eadie-Hofstee plots of imipramine
N-glucuronidation in human liver microsomes were
biphasic. For the high-affinity component, the
Km was 97.2 ± 39.4 µM and the
Vmax was 0.29 ± 0.03 nmol/min/mg of
protein. For the low-affinity component, the
Km was 0.70 ± 0.29 mM and the
Vmax was 0.90 ± 0.28 nmol/min/mg of
protein. The imipramine N-glucuronosyltransferase
activities were not detectable in two samples of human jejunum
microsomes. Among recombinant UDP-glucuronosyltransferases
(UGTs) in baculovirus-infected insect cells (Supersomes or Bacurosomes)
or human B-lymphoblastoid cells tested in the present study (UGT1A1,
UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and
UGT2B15), only UGT1A4 showed imipramine
N-glucuronosyltransferase activity. The activity in UGT1A4 Supersomes was higher than that in recombinant UGT1A4 expressed in human B-lymphoblastoid cells at all imipramine concentration tested.
The kinetics of imipramine N-glucuronidation in UGT1A4 Supersomes did not fit the Michaelis-Menten plot, showing a
Km of >1 mM. In contrast, in UGT1A4
expressed in human B-lymphoblastoid cells,
Km was 0.71 ± 0.36 mM and the
Vmax was 0.11 ± 0.03 nmol/min/mg of
protein. Interindividual differences in the imipramine
N-glucuronidation in liver microsomes from 14 humans
were at most 2.5-fold. The imipramine
N-glucuronosyltransferase activities in 11 human liver microsomes were significantly (r = 0.817, P < 0.005) correlated with the
glucuronosyltransferase activities of trifluoperazine, a typical
substrate of UGT1A4. This is the first report of the biphasic kinetics
of imipramine N-glucuronide in human liver microsomes.
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