Although it has long been recognized that many antihypertensive drugs exhibit large intersubject variability in their disposition characteristics, the concept that this translates into a high variability in response has largely been ignored. Thus, too often in the past, research into antihypertensive drugs has ignored the importance of underlying plasma drug concentrations and has sought to attribute the variability in antihypertensive response to factors such as age and plasma renin activity. In studies with hypertensive patients in which pharmacokinetic and pharmacodynamic indices have been integrated, we have demonstrated that the intersubject variability in the pharmacokinetics of verapamil, nifedipine, enalapril, and amlodipine is directly related to the variability in blood pressure response at steady state. The characteristic low variability in the peak and predose, steady-state plasma concentrations associated with amlodipine are reflected in a correspondingly low variability in the blood pressure response. In addition, using the trough-to-peak, steady-state, blood pressure response as an index of 24-h duration of action, amlodipine exhibited significantly higher values with lower variability (66 +/- 11%) when compared to verapamil (47 +/- 13%), nifedipine (48 +/- 9%) and enalapril (44 +/- 15%). Concentration-effect analyses of all four drugs revealed that the antihypertensive response could be related to circulating drug concentrations and that the response following administration of the first dose correlated well with the response following long-term treatment.