Tissue levels, tissue angiotensin converting enzyme inhibition and antihypertensive effect of the novel antihypertensive agent alacepril in renal hypertensive rats.

Tissue levels, tissue angiotensin I converting enzyme (ACE) inhibition and hypotension were examined 20 min, 1, 5 and 14 h after oral administration of 1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine (alacepril, DU-1219) (37.5 mg (92 mumol)/kg) or 1-[(S)-3-mercapto-2-methylpropanoyl]-L-proline (captopril) (20.0 mg (92 mumol)/kg) in renal hypertensive rats, using 14C-labeled compounds. Alacepril exerted a more gradual and more sustained antihypertensive effect than captopril. The maximal hypotension was observed 1 and 5 h after administration of captopril and alacepril, respectively. After administration of [14C]captopril, serum level reached the maximum at 20 min and then decreased rapidly. After administration of [14C]alacepril, serum level reached the maximum at 1 h and decreased more slowly than after [14C]captopril. Time course patterns of tissue levels were essentially in parallel with those of serum levels. Captopril exerted the maximal reduction of ACE activity in tissues 20 min after oral administration and thereafter, the reduction was diminished with time rapidly. [14C]Alacepril showed gradual reduction (the maximum at 1 h) and recovery of ACE activity relative to captopril. After oral administration of [14C]alacepril, tissue unbound fractions contained captopril and its derived metabolites while serum unbound fraction contained the intermediate metabolite desacetyl-alacepril (DU-1227) as well. Correlations between ACE inhibition and tissue levels and between changes in tissue ACE inhibition and in blood pressure with time after oral administration of the two agents were discussed. Furthermore, the direct comparison of alacepril and captopril was attempted by the difference in blood pressures and in ACE inhibitions induced after oral administration of the agents.