Retigabine N-glucuronidation and its potential role in enterohepatic circulation.

Article Details

Citation

Hiller A, Nguyen N, Strassburg CP, Li Q, Jainta H, Pechstein B, Ruus P, Engel J, Tukey RH, Kronbach T

Retigabine N-glucuronidation and its potential role in enterohepatic circulation.

Drug Metab Dispos. 1999 May;27(5):605-12.

PubMed ID
10220490 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
EzogabineUDP-glucuronosyltransferase 1-1ProteinHumans
Unknown
Substrate
Details
EzogabineUDP-glucuronosyltransferase 1-3ProteinHumans
Unknown
Substrate
Details
EzogabineUDP-glucuronosyltransferase 1-4ProteinHumans
Unknown
Substrate
Details
EzogabineUDP-glucuronosyltransferase 1-9ProteinHumans
Unknown
Substrate
Details