title: Retigabine N-glucuronidation and its potential role in enterohepatic circulation.
abstract: The metabolism of retigabine in humans and dogs is dominated by N-glucuronidation (), whereas in rats, a multitude of metabolites of this new anticonvulsant is observed (). The comparison of the in vivo and in vitro kinetics of retigabine N-glucuronidation in these species identified a constant ratio between retigabine and retigabine N-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 retigabine N-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 the N-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.
authors.affiliation: Corporate Research & Development ASTA Medica Group, Meissner Strasse 191, Radebeul, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Hiller
authors.forename: N
authors.initials: N
authors.lastname: Nguyen
authors.forename: C P
authors.initials: CP
authors.lastname: Strassburg
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.forename: H
authors.initials: H
authors.lastname: Jainta
authors.forename: B
authors.initials: B
authors.lastname: Pechstein
authors.forename: P
authors.initials: P
authors.lastname: Ruus
authors.forename: J
authors.initials: J
authors.lastname: Engel
authors.forename: R H
authors.initials: RH
authors.lastname: Tukey
authors.forename: T
authors.initials: T
authors.lastname: Kronbach
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism* / Q000494:pharmacology; D002219:Carbamates / Q000378:metabolism* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004764:Enterohepatic Circulation / Q000502:physiology*; D005965:Glucuronates / Q000378:metabolism; D006801:Humans; D007206:Individuality; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010655:Phenylenediamines / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011911:Rats, Gunn; D017208:Rats, Wistar
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; D005965:Glucuronates; D007527:Isoenzymes; D010655:Phenylenediamines; C101866:ezogabine