PT  - JOURNAL ARTICLE
AU  - Lautala, Pia
AU  - Ethell, Brian T.
AU  - Taskinen, Jyrki
AU  - Burchell, Brian
TI  - The Specificity of Glucuronidation of Entacapone and Tolcapone by Recombinant Human Udp-Glucuronosyltransferases
DP  - 2000 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 1385--1389
VI  - 28
IP  - 11
4099  - http://dmd.aspetjournals.org/content/28/11/1385.short
4100  - http://dmd.aspetjournals.org/content/28/11/1385.full
SO  - Drug Metab Dispos2000 Nov 01; 28
AB  - 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 mg−1, 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 lowerKm value for both entacapone and tolcapone than UGT2B15 and UGT2B7 whose contribution is minor by comparison. Entacapone showed a 3 to 4 times higher Vmaxvalue and a 4 to 6 times lower Km value compared with those of tolcapone both in UGT1A9 cell lysates and in human liver microsomes. The American Society for Pharmacology and Experimental Therapeutics