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Vol. 28, Issue 11, 1385-1389, November 2000
Department of Pharmacy, Division of Pharmaceutical Chemistry,
University of Helsinki, Finland (P.L., J.T.); and Department of
Molecular and Cellular Pathology, Ninewells Hospital and Medical
School, Dundee, Scotland (B.T.E., B.B.)
The COMT inhibitors entacapone and tolcapone are rapidly
metabolized in vivo, mainly by glucuronidation. In this work, the main
UGT isoforms responsible for their glucuronidation in vitro were
characterized by using a subset of representative cloned and expressed
human UGT isoforms. Entacapone in particular was seen to be an
exceptionally good substrate for UGT1A9 with an even higher reaction
velocity value at 500 µM substrate concentration compared with that
of the commonly used substrate, propofol (1.3 and 0.78 nmol
min
1 mg1, respectively). Neither entacapone
nor tolcapone was glucuronidated by UGT1A6. Tolcapone was not
detectably glucuronidated by UGT1A1, and the rate of glucuronidation of
entacapone was also low by this isoform. However, UGT1A1 was the only
UGT capable of catalyzing the formation of two glucuronides of the
catecholic entacapone. Both COMT inhibitors were glucuronidated at low
rates by the representative members of the UGT2B family, UGT2B7 and
UGT2B15. Michaelis-Menten parameters were determined for entacapone and
tolcapone using recombinant human UGT isoforms and human liver
microsomes to compare the kinetic properties of the two COMT
inhibitors. The kinetic data illustrates that UGT1A9 exhibited a much
greater rate of glucuronidation and a far lower
Km value for both entacapone and tolcapone
than UGT2B15 and UGT2B7 whose contribution is minor by comparison.
Entacapone showed a 3 to 4 times higher Vmax
value and a 4 to 6 times lower Km value
compared with those of tolcapone both in UGT1A9 cell lysates and in
human liver microsomes.
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