Glucuronidation of antiallergic drug, Tranilast: identification of human UDP-glucuronosyltransferase isoforms and effect of its phase I metabolite.

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Citation

Katoh M, Matsui T, Yokoi T

Glucuronidation of antiallergic drug, Tranilast: identification of human UDP-glucuronosyltransferase isoforms and effect of its phase I metabolite.

Drug Metab Dispos. 2007 Apr;35(4):583-9. doi: 10.1124/dmd.106.013706. Epub 2007 Jan 12.

PubMed ID
17220234 [ View in PubMed
]
Abstract

Tranilast is an oral antiallergic agent widely used in Japan. Recently, in Western populations, hyperbilirubinemia induced by tranilast was suspected during clinical trials. Tranilast has been reported to be mainly metabolized to a glucuronide and a phase I metabolite, 4-demethyltranilast (N-3). In the present study, we investigated the in vitro metabolism of tranilast in human liver and jejunum microsomes and recombinant UDP-glucuronosyltransferases (UGTs). The glucuronidation of tranilast was clarified to be mainly catalyzed by UGT1A1 in human liver and intestine. The K(m) values of tranilast glucuronosyltransferase activity were 51.5, 50.6, and 38.0 microM in human liver microsomes, human jejunum microsomes, and recombinant UGT1A1, respectively. The V(max) values were 10.4, 42.9, and 19.7 pmol/min/mg protein in human liver microsomes, human jejunum microsomes, and recombinant UGT1A1, respectively. When the intrinsic clearance was calculated using the in vitro kinetic parameters, microsomal protein content, and weight of tissues, tranilast glucuronosyltransferase activity was 2.5-fold higher in liver than in intestine. Tranilast glucuronosyltransferase activity was strongly inhibited by bilirubin, a typical UGT1A1 substrate, and N-3, indicating that the phase I metabolite could affect the tranilast glucuronosyltransferase activity. In the case of N-3 formation, the K(m) and V(max) values were 37.1 microM and 27.6 pmol/min/mg protein in human liver microsomes. The bilirubin glucuronosyltransferase activity was strongly inhibited by both tranilast and N-3, suggesting that tranilast-induced hyperbilirubinemia would be responsible for the inhibition by tranilast and N-3 of the bilirubin glucuronosyltransferase activity, as would the UGT1A1 genotype.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
TranilastCytochrome P450 2C9ProteinHumans
No
Substrate
Details
Drug Interactions
DrugsInteraction
Acenocoumarol
Tranilast
The risk or severity of bleeding can be increased when Tranilast is combined with Acenocoumarol.
Warfarin
Tranilast
The risk or severity of bleeding can be increased when Tranilast is combined with Warfarin.