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-[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.


OBJECTIVE
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.


METHODS
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.


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 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.


CONCLUSIONS
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.
Rousso
P
P
Division de Pharmacologie clinique, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.
Buclin
T
T
Nussberger
J
J
Brunner-Ferber
F
F
Brunner
H R
HR
Biollaz
J
J
D000284:Administration, Oral; D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001552:Benzazepines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D011480:Protease Inhibitors / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012083:Renin / Q000097:blood*; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D011480:Protease Inhibitors; D011725:Pyridines; C085683:MDL 100240; D012083:Renin