Dabigatran acylglucuronide, the major human metabolite of dabigatran: in vitro formation, stability, and pharmacological activity.

Article Details

Citation

Ebner T, Wagner K, Wienen W

Dabigatran acylglucuronide, the major human metabolite of dabigatran: in vitro formation, stability, and pharmacological activity.

Drug Metab Dispos. 2010 Sep;38(9):1567-75. doi: 10.1124/dmd.110.033696. Epub 2010 Jun 15.

PubMed ID
20551237 [ View in PubMed
]
Abstract

Glucuronidation of the carboxylate moiety is the major human metabolic pathway of dabigatran (beta-alanine, N-[[2-[[[4-(aminoiminomethyl)phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]c arbonyl]-N-2-pyridinyl). It results in the formation of the 1-O-acylglucuronide. Four isomeric acylglucuronides of dabigatran were isolated and purified from urine of dosed rhesus monkeys. NMR analysis confirmed the structures of the four metabolites as the 1-O-acylglucuronide (beta anomer) and the 2-O-, 3-O-, and 4-O-acylglucuronides (alpha and beta anomers). Experiments with the purified 1-O-acylglucuronide and its isomeric rearrangement products revealed equipotent prolongation of the activated partial thromboplastin time compared with dabigatran. The 1-O-acylglucuronide, in addition to minor hydrolysis to the aglycon, underwent nonenzymatic acyl migration in aqueous solution, resulting in the formation of the 2-O-, 3-O-, and 4-O-acylglucuronides with an apparent half-life of 1 h (37 degrees C, pH 7.4). The glucuronidation of dabigatran was catalyzed by human hepatic and intestinal microsomes with K(m) values in the range of 180 to 255 and 411 to 759 microM, respectively. Three UDP-glucuronosyltransferases (UGTs), namely, UGT1A9, UGT2B7, and UGT2B15, exhibited glucuronidation of dabigatran. Based on a comparison of the in vitro intrinsic clearances, UGT2B15 was considered the major contributor to the glucuronidation of dabigatran. The major contribution of UGT2B15 and the minor contribution of at least two more UGT enzymes together with the lack of potent inhibition of dabigatran glucuronidation by several potential UGT inhibitors indicate a low risk of interaction by co-medications on dabigatran glucuronidation in the clinic.

DrugBank Data that Cites this Article

Drugs
Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
Dabigatran etexilateProthrombinProteinHumans
Yes
Inhibitor
Details
Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
Dabigatran etexilateUDP-glucuronosyltransferase 1-9ProteinHumans
Unknown
Substrate
Details
Dabigatran etexilateUDP-glucuronosyltransferase 2B15ProteinHumans
Unknown
Substrate
Details
Dabigatran etexilateUDP-glucuronosyltransferase 2B7ProteinHumans
Unknown
Substrate
Details