Steady-state pharmacokinetics and pharmacodynamics of imidaprilat, an active metabolite of imidapril, a new angiotensin-converting enzyme inhibitor in spontaneously hypertensive rats.

Imidapril, a new angiotensin-converting enzyme (ACE) inhibitor, was infused subcutaneously at the rates of 9, 30, 90, and 300 micrograms/rat/day for 4 weeks via an osmotic pump implanted under the skin in the back of male spontaneously hypertensive rats (SHRs). Plasma concentrations of imidaprilat as an active metabolite of imidapril, systolic blood pressure (SBP), and plasma ACE activity were determined periodically. These results were also compared with those of enalapril. The plasma concentrations of an active metabolite of both the imidapril and enalapril groups increased according to the doses and showed almost the same plasma concentrations at the same doses. Both groups significantly inhibited plasma ACE activity and reduced SBP, and these actions were maintained for 4 weeks. At the lowest dose studied (9 micrograms/rat/day), imidapril was more potent than enalapril in inhibiting plasma ACE (maximum 2.5-fold difference), but this difference was reduced at higher doses. In contrast, significant differences in SBP effects were observed only at the highest dose studied (300 micrograms/rat/day). Also, the imidapril group significantly decreased the relative heart weight at the rate of 300 micrograms/rat/day. Furthermore, good correlations between plasma imidaprilat concentration and plasma ACE activity or SBP were observed, suggesting that plasma concentration may be a useful marker of pharmacological effects. However, a poor relationship between plasma ACE activity and SBP for enalapril was observed, suggesting that this may not be an adequate marker of pharmacologic efficacy of ACE inhibitors in general. The clinical relevance of these findings is not known at present.