Effect of enalapril on the in vitro and in vivo peptidyl cleavage of a potent VLA-4 antagonist

Abstract

BIO1211 is a small peptidyl potent antagonist of the activated form of α4β1 integrin. The effect of enalapril on the in vitro and in vivo cleavage of BIO1211 was investigated. In heparinized blood, plasma and rat liver, lung and intestinal homogenates, BIO1211 was converted rapidly to BIO1588 by hydrolytic cleavage of the terminal dipeptide moiety. This cleavage could be inhibited by EDTA and the ACE inhibitor, enalaprilat, the de-esterified acid derivative of enalapril. Enalaprilat inhibited the hydrolysis of BIO1211 in a concentration-dependent manner with IC₅₀ values of 2 nM in human and sheep plasma and 10 nM in rat plasma. In rat lung homogenate supernatant, the maximum inhibition of the conversion of BIO1211 to BIO1588 was ∼80% at 1 µM with no further effect up to 100 µM of enalaprilat. Following a concomitant IV administration of enalapril and BIO1211 at 3 mg/kg each, the AUC and the half-life values of BIO1211 increased 18- and 10-fold, respectively. The AUC of BIO1588 decreased ∼2-fold with no change in its plasma half-life. When rats were dosed intravenously with enalapril followed by an intratracheal dose of BIO1211, there was ∼2.5-fold decrease in the AUC of BIO1588 and a 2.4-fold increase in its plasma half-life.

Key Words::

• VLA-4 antagonist
• enalapril
• peptide cleavage

Acknowledgements

We thank Dr S. H. Lee Chiu and Dr Art Patchett from Merck Research Laboratories for helpful discussions. We also thank Francine Brown and Eddi Kwan from Biogen Inc. for technical assistance.