STUDIES WITH LOW-DOSE INTRAVENOUS DIACID ACE INHIBITOR (PERINDOPRILAT) INFUSIONS IN NORMOTENSIVE MALE-VOLUNTEERS

1 Intravenous ACE inhibitor therapy is of increasing importance in the treatment of patients with unstable heart failure after myocardial infarction. Available pharmacokinetic and concentration effect data with this route of administration are limited. 2 The pharmacokinetics and blood pressure responses to perindoprilat were studied during prolonged low dose (1 mg) infusions in eight normotensive salt replete male volunteers. 3 Subjects received randomised, single (subject) blinded therapy with saline placebo (30 ml) over 3 h or active treatment (1 mg in 30 ml) over 1 h, 3 h or 6 h by constant rate infusion. 4 Significant falls in blood pressure greater than placebo were noted with active infusions without changes in heart rate. Mean maximal plasma perindoprilat concentrations reflected the rate of infusion (1 h, 51.5 +/- 11.4 ng ml-1; 3 h, 30.4 +/- 8.4 ng ml-1; 6 h 19.0 +/- 4.0 ng ml-1) and mean maximal plasma ACE inhibition was less with slower infusions (1 h, 95.7 +/- 0.5%; 3 h 92.3 +/- 2.7%; 6 h 87.4 +/- 5.1%, P < 0.013). 5 Concentration-time profiles showed a sigmoid drug accumulation profile with delay in the early accumulation of drug particularly during the 3 h and 6 h infusions. The pharmacokinetic data was assessed by statistical comparison of a hierarchy of standard compartmental models and non linear saturable binding models. A non linear model incorporating elements to describe both tissue and plasma binding of the drug provided the best fit to observed data. 6 Low dose constant rate infusions are a means of optimising intravenous ACE inhibitor therapy to allow individual dose titration. This has clinical relevance to the treatment of unstable patients who are potentially vulnerable to a marked fall in blood pressure. Controlled low dose therapy may also allow clearer definition of tissue drug distribution, tissue ACE inhibition and the relationship of these parameters to haemodynamic effect.