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

• Published in: European journal of clinical pharmacology Vol. 55; no. 10; pp. 749 - 754
• Main Authors: ROUSSO, P, BUCLIN, T, NUSSBERGER, J, BRUNNER-FERBER, F, BRUNNER, H. R, BIOLLAZ, J
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer 01-01-2000; Berlin Springer Nature B.V
• Subjects: Administration, Oral; Adult; Angiotensin-Converting Enzyme Inhibitors - administration & dosage; Angiotensin-Converting Enzyme Inhibitors - pharmacokinetics; Antihypertensive agents; Benzazepines - administration & dosage; Benzazepines - pharmacokinetics; Biological and medical sciences; Biological Availability; Cardiovascular system; Dose-Response Relationship, Drug; Double-Blind Method; Drug dosages; Humans; Infusions, Intravenous; Male; Medical sciences; Peptides; Pharmacology. Drug treatments; Protease Inhibitors - pharmacokinetics; Pyridines - administration & dosage; Pyridines - pharmacokinetics; Renin - blood; Time Factors; Human; Healthy subject; Enzyme; Oral administration; Enzyme inhibitor; Atrial natriuretic peptide; Bioavailability; Multiple dose; Peptidases; Endopeptidase; Hydrolases; Pharmacokinetics; ACE inhibitor
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s002280050009

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-[4alpha,7alpha(R(*)),12bbeta]]-) is a molecule possessing an inhibiting ability on both angiotensin converting enzyme (ACE) and neutral endopeptidase, the enzyme responsible for atrial natriuretic peptide (ANP) degradation. Such a dual mechanism of action presents a potential clinical interest for the treatment of hypertension and congestive heart failure.
To evaluate the bioavailability of MDL 100,240 and its accumulation over repeated oral administration, using ACE inhibition as a surrogate for plasma drug level and determining its profile after oral and i.v. administration.
First, in an open, one-period, single-dose study, the ACE inhibition 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 group of four subjects received q.d., over 8 days, 2.5, 10 or 20 mg of MDL 100,240 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 activity was monitored up to 72 h after the last dose of MDL 100,240.
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 20 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 accumulation 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.
MDL 100,240 (oral solution) has a good bioavailability, as estimated by ACE inhibition, and no drug accumulation seems to occur over 8 days with the 10-mg and 20-mg doses, but a slight rise in the trough level is observed with the 2. 5-mg dose.