Holenarsipur_2015_Biopharm.Drug.Dispos_36_385

Reference

Title : Absorption and cleavage of enalapril, a carboxyl ester prodrug, in the rat intestine: In vitro, in situ intestinal perfusion, and portal vein cannulation models - Holenarsipur_2015_Biopharm.Drug.Dispos_36_385
Author(s) : Holenarsipur VK , Gaud N , Sinha J , Sivaprasad S , Bhutani P , Subramanian M , Singh SP , Arla R , Paruchury S , Sharma T , Marathe P , Mandlekar S
Ref : Biopharmaceutics & Drug Disposition , 36 :385 , 2015
Abstract :

In recent years prodrug strategy has been extensively used to improve the pharmacokinetic properties of compounds exhibiting poor bioavailability. Mechanistic understanding of absorption and the role of intestine and liver in the activation of oral prodrugs is crucial. Enalapril, a carboxyl ester prodrug, is reported to be metabolized by human carboxylesterase-1 (CES1) but not by carboxylesterase-2 (CES2) to its active metabolite enalaprilat. Further, it has been reported that the small intestines of both rat and human contain mainly the CES2. The objective of this work was to understand whether enalapril remains unchanged as it gets absorbed through the intestine into the portal circulation. It was evaluated using different intestinal preparations, in situ intestinal perfusion experiment, and portal vein cannulated rat model. No turnover of enalapril was seen with commercial rat intestinal S9 and microsomes, but reasonable turnover was observed with freshly prepared rat intestinal and mucosal homogenate and S9. In the intestinal perfusion study, both enalapril and enalaprilat were observed in the mesenteric plasma with the data suggesting 32% hydrolysis of enalapril in the intestine. In the portal vein cannulated rat, about 51% of enalapril absorbed into intestine was converted to enalaprilat. Overall, we have demonstrated that even though enalapril has been shown to be a specific substrate for CES1, it is converted to enalaprilat to a significant extent in the intestine. Such experimental techniques can be applied by other scientific groups who are working on prodrugs to determine the region and extent of activation. This article is protected by copyright. All rights reserved.

PubMedSearch : Holenarsipur_2015_Biopharm.Drug.Dispos_36_385
PubMedID: 25832562

Related information

Substrate Enalapril

Citations formats

Holenarsipur VK, Gaud N, Sinha J, Sivaprasad S, Bhutani P, Subramanian M, Singh SP, Arla R, Paruchury S, Sharma T, Marathe P, Mandlekar S (2015)
Absorption and cleavage of enalapril, a carboxyl ester prodrug, in the rat intestine: In vitro, in situ intestinal perfusion, and portal vein cannulation models
Biopharmaceutics & Drug Disposition 36 :385

Holenarsipur VK, Gaud N, Sinha J, Sivaprasad S, Bhutani P, Subramanian M, Singh SP, Arla R, Paruchury S, Sharma T, Marathe P, Mandlekar S (2015)
Biopharmaceutics & Drug Disposition 36 :385