Intestinal absorption pathways of lisinopril: Mechanistic investigations

Abstract

Lisinopril is an antihypertensive drug with poor intestinal permeability. Enhancement of intestinal absorption depends on a clear understanding of the permeation pathways and absorption mechanisms. Unfortunately, these are not fully elucidated for lisinopril. Accordingly, the aim was to determine lisinopril permeation pathways and obstacles limiting membrane transport with subsequent nomination of appropriate permeation enhancers. This employed an in situ rabbit intestinal perfusion technique, which revealed site-dependent absorptive clearance (PeA/L) from a lisinopril simple solution (5 μg/ml), with paracellular absorption playing a role. Regional drug permeability ranked as colon> duodenum> jejunum> ileum opposing intestinal expression rank of P-glycoprotein (P-gp) efflux transporters. Duodenal and jejunal perfusion of a higher lisinopril concentration (50 μg/ml) reflected saturable absorption, suggesting carrier-mediated transport. The effect of piperine and verapamil as P-gp inhibitors on intestinal absorption of lisinopril was investigated. Coperfusion with either piperine or verapamil significantly enhanced lisinopril absorption, with enhancement being dominant in the ileum segment. This supported the contribution of P-gp transporters to poor lisinopril permeability. On the other hand, coperfusion of lisinopril with zinc acetate dihydrate significantly multiplied lisinopril PeA/L by 2.3- and 6.6-fold in duodenum and ileum segments, respectively, through magnifying intestinal water flux. The study explored the barriers limiting lisinopril intestinal absorption. Moreover, the study exposed clinically relevant lisinopril interactions with common coadministered cargos that should be considered for an appropriate lisinopril regimen. However, this requires further in vivo verification.