RT Journal Article
SR Electronic
T1 Retigabine <em>N</em>-Glucuronidation and Its Potential Role in Enterohepatic Circulation
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 605
OP 612
VO 27
IS 5
A1 Hiller, Anita
A1 Nguyen, Nghia
A1 Strassburg, Christian P.
A1 Li, Qing
A1 Jainta, Harald
A1 Pechstein, Birgit
A1 Ruus, Peter
A1 Engel, Jürgen
A1 Tukey, Robert H.
A1 Kronbach, Thomas
YR 1999
UL http://dmd.aspetjournals.org/content/27/5/605.abstract
AB The metabolism of retigabine in humans and dogs is dominated byN-glucuronidation (McNeilly et al., 1997), whereas in rats, a multitude of metabolites of this new anticonvulsant is observed (Hempel et al., 1999). The comparison of the in vivo and in vitro kinetics of retigabine N-glucuronidation in these species identified a constant ratio between retigabine and retigabineN-glucuronide in vivo in humans and dog. An enterohepatic circulation of retigabine in these species is likely to be the result of reversible glucuronidation-deglucuronidation reactions. Rats did not show such a phenomenon, indicating that enterohepatic circulation of retigabine via retigabineN-glucuronide does not occur in this species. In the rat, 90% of retigabine N-glucuronidation is catalyzed by UDP-glucuronosyltransferase (UGT)1A1 and UGT1A2, whereas family 2 UGT enzymes contribute also. Of ten recombinant human UGTs, only UGTs 1A1, 1A3, 1A4, and 1A9 catalyzed theN-glucuronidation of retigabine. From the known substrate specificities of UGT1A4 toward lamotrigine and bilirubin and our activity and inhibition data, we conclude that UGT1A4 is a major retigabine N-glucuronosyl transferase in vivo and significantly contributes to the enterohepatic cycling of the drug. The American Society for Pharmacology and Experimental Therapeutics