Pharmacoscintigraphic assessment of the regional drug absorption of the dual angiotensin-converting enzyme/neutral endopeptidase inhibitor, M100240, in healthy volunteers.

M100240 is the thioester of MDL 100,173, a dual angiotensin-converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor currently in phase II development. The purpose of this study was to evaluate the relative bioavaibility of M100240 in various regions of the gastrointestinal tract using the Enterion capsule, a noninvasive radiocontrolled device providing targeted drug delivery, to explore the absorption characteristics of M100240 in healthy volunteers. In addition, the absolute bioavailability of an immediate-release formulation of M100240 was assessed. Pharmacokinetic data were obtained from 13 healthy subjects in an open-label, single-dose, randomized, five-period crossover study. Treatments included 25 mg M100240 administered via short intravenous infusion, oral immediate-release tablet administration, and oral Enterion capsule delivery of drug substance to the proximal small bowel, distal small bowel, and ascending colon. Each treatment was separated by a 14-day drug-free washout period. The localization of the Enterion capsule in the gastrointestinal tract was monitored using scintigraphic imaging. M100240 and MDL 100,173 plasma concentrations were quantified using a validated LC/MS/MS method, and pharmacokinetic parameters were calculated using noncompartmental methods. The estimates of relative bioavailability in the proximal small bowel, distal small bowel, and ascending colon relative to the oral immediate-release tablet are approximately 94%, 97%, and 41%, respectively. M100240 is primarily absorbed throughout the proximal and distal small bowel with modest absorption in the ascending colon. The absolute bioavailability estimate of the M100240 immediate-release formulation is 49%. These data characterize the fundamental in vivo performance attributes of M100240, thereby providing an approach for optimizing prototype modified-release formulations for this compound.