Sequential hydrolysis of dabigatran etexilate to its active metabolite by human carboxylesterase 1 and 2 (1064.6)

Abstract

The direct thrombin inhibitor dabigatran etexilate (DABE) is a double prodrug that undergoes near complete presystemic conversion to the active dabigatran (DAB) metabolite after oral dosing in humans. Based on the ethyl ester and carbamate ester groups in its structure and previous reports that DABE is hydrolyzed by serine esterases, we hypothesized that human carboxylesterase‐1 (CES1) and carboxylesterase 2 (CES2) are responsible for the hydrolysis of DABE to DAB. DABE enzyme kinetics in human recombinant CES1 and CES2, human intestinal microsomes (HIM) and human liver S9 fractions (HLS9) were performed. Sequential hydrolysis of DABE in HIM and HLS9 was also conducted to simulate the in vivo disposition of DABE after oral administration. We found that hydrolysis of the DABE double prodrug by both CES1 (ethyl ester) and CES2 (carbamate ester) is required for the formation of DAB and that complete conversion of DABE to DAB was achieved by sequential hydrolysis in HIM and then HLS9. Based on this scheme, we propose that the major pathway responsible for the presystemic formation of DAB is hydrolysis of the DABE carbamate ester by CES2 in the intestines followed by conversion to DAB in the liver by CES1‐mediated ester hydrolysis. This proposed pathway is consistent with the near total presystemic conversion of DABE to DAB and the sequential exposure to CES2 and CES1 following oral dosing based on high expression levels of CES2 and CES1 in the intestines and liver, respectively.Grant Funding Source: National Institutes of Health National Institute of General Medical Sciences