Pharmacokinetic and pharmacodynamic variability largely account for interindividual differences in the response to
antihypertensive drugs including
angiotensin converting enzyme inhibitors. The factors determining the response to
enalapril have been investigated in a placebo-controlled study in
essential hypertension. The effects of placebo, the initial dose of
enalapril, and long-term (1 and 6 weeks) treatment with
enalapril were studied in 13 subjects. By using an integrated kinetic-dynamic model that incorporates a parameter for saturable protein binding, individual responses for blood pressure reduction and
angiotensin converting enzyme inhibition were characterized in terms of the maximum effect (Emax) and the
drug concentration required to produce 50% of Emax (Ce50). In individual subjects, plasma
enalaprilat concentrations could be correlated with falls in blood pressure and changes in plasma
angiotensin converting enzyme activity. For the group, Emax was -46.1 +/- 16.5 and -19.7 +/- 3.8 mm Hg for systolic and diastolic blood pressure, respectively, and the corresponding Ce50 values were 66.1 +/- 20.2 and 61.6 +/- 22.5 ng/ml. For
angiotensin converting enzyme inhibition, Emax (%) and Ce50 (ng/ml) were, respectively, 102.4 +/- 5 and 19.8 +/- 13 after the first dose, 103 +/- 5 and 33.4 +/- 20.3 after 1 week, and 101.3 +/- 2.2 and 31.3 +/- 18.9 after 6 weeks. There was no relation between the responsiveness to
enalapril (Emax or Ce50) and patient age or plasma
renin activity, but there was a significant positive correlation between Emax and the pretreatment blood pressure. In individual subjects, Emax (first dose) was directly correlated with Emax after 1 and 6 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)