Bioavailability of repeated oral administration of MDL 100,240, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase in healthy volunteers

Background: MDL 100,240 (pyrido[2,1-a] [2] benzazepine-4-carboxylic acid,7- [[2-(acetylthio)-1-oxo-3 -phenylpropyl]amino]- 1,2,3,4,6,7,8,12b-octahydro- 6-oxo, [4S-[4 alpha,7 alpha(R*),12b beta]]-) is a molecule possessing an in hibiting ability on both angiotensin converting enzyme (ACE) and neutral en dopeptidase, the enzyme responsible for atrial natriuretic peptide (ANP) de gradation. Such a dual mechanism of action presents a potential clinical in terest for the treatment of hypertension and congestive heart failure. Objectives: To evaluate the bioavailability of MDL 100,240 and its accumula tion over repeated oral administration, using ACE inhibition as a surrogate for plasma drug level and determining its profile after oral and i.v. admi nistration. Methods: First, in an open, one-period, single-dose study, the ACE inhibiti on profile was characterised following a 12.5 mg MDL 100,240 i.v. infusion. Second, in a three-group, parallel, randomised, double-blind study, each g roup of four subjects received q.d., over 8 days, 2.5, 10 or 20 mg of MDL 1 00,240 orally. The ACE inhibition profile was determined on day 1 and day 8 . Trough plasma ACE was measured on days 2, 3 and 4. The recovery of ACE ac tivity was monitored up to 72 h after the last dose of MDL 100,240. Results: ACE inhibition profile was similar on day 1 and day 8, and trough inhibition remained unchanged after the 8 days of treatment with 10 mg or 2 0 mg. Following repeated 2.5-mg ingestion, trough inhibition increased from 33% to 44% after the eighth dose. The oral bioavailability of MDL 100,240 was estimated at 85%, not statistically different from 100%. The accumulati on ratio at steady state was estimated at 112%. Expressing the accumulation ratio in terms of half-life, a t(1/2) Of 0.31 days or 7.5 h was estimated. Conclusion: MDL 100,240 (oral solution) has a good bioavailability, as esti mated by ACE inhibition, and no drug accumulation seems to occur over 8 day s with the 10-mg and 20-mg doses, but a slight rise in the trough level is observed with the 2.5-mg dose.