Pharmacokinetic and dynamic interactions of the angiotensin-converting enzyme inhibitor imidapril with hydrochlorothiazide, bisoprolol and nilvadipine.
OBJECTIVE
The pharmacokinetic and dynamic interactions of the angiotensin-converting enzyme (ACE) inhibitor imidapril with other therapeutic principles used in hypertension and heart failure were evaluated.


METHODS
In three separate, double-blind, placebo-controlled, four-way cross-over studies in healthy volunteers (n = 16 each), single oral doses of imidapril 10 mg (I), hydrochlorothiazide 12.5 mg (H), bisoprolol 5 mg (B) and nilvadipine 8 mg (N) were administered as monotherapies, and in IH, IB and IN combinations. Plasma concentrations of imidaprilat and H were followed up to 48 h, those of B and N up to 24 h and area under the concentration time curve (AUC), maximum plasma concentration (Cmax) and time to Cmax (tmax) were determined. Blood pressure (BP), heart rate (HR) and non-invasive haemodynamics [total peripheral resistance (TPR, N and H), systolic time intervals (STI, N and H), and plasma renin activity (PRA)] were assessed up to 24 h.


RESULTS
There were no pharmacokinetic interactions between I plus H, B or N. Bioequivalence between single and combined administrations was verified for all investigational compounds [AUC point estimates (90% confidence interval CI): imidaprilat IH 109% (97.8, 122.8); IB 99.6% (91.2, 109.4); IN 105.7% (92.1, 121.3); H 96.6% (92.5, 100.8); B 103% (100.2, 105.8); N 98% (89, 108)]. The haemodynamic effects were mostly additive and without relevant pharmacodynamic interactions. I significantly reduced the BP by 5-8 mmHg, B by 4-8 mmHg and N by 4-6 mmHg. In addition, H induced a significant reduction of the preload as seen from STI, and B significantly reduced HR (-5 bpm). N induced a significant decrease in TPR (about 15% of baseline values) and showed corresponding changes in STI. PRA increased significantly following I alone (1.5-2.0 ng/ml/h), as well as combined with N (2.5 ng/ ml/h) or H (3.1 ng/ml/h). This increase was clearly blunted by the co-administration of B (0.6 ng/ml/h).


CONCLUSIONS
The combination of imidapril with a diuretic, beta-adrenoceptor antagonist or calcium-channel blocker seems a reasonable and safe treatment option when striving for additive pharmacodynamic effects not accompanied by relevant pharmacokinetic interactions.
Breithaupt-Grögler
K
K
Centre for Cardiovascular Pharmacology, ZeKaPha GmbH, Mainz, Germany.
Ungethüm
W
W
Meurer-Witt
B
B
Belz
G G
GG
D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D017298:Bisoprolol / Q000493:pharmacokinetics / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D004232:Diuretics; D004311:Double-Blind Method; D004347:Drug Interactions; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006852:Hydrochlorothiazide / Q000493:pharmacokinetics / Q000494:pharmacology*; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D048289:Imidazolidines; D008297:Male; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D049993:Sodium Chloride Symporter Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004232:Diuretics; D007093:Imidazoles; D048289:Imidazolidines; D049993:Sodium Chloride Symporter Inhibitors; C035100:nilvadipine; D006852:Hydrochlorothiazide; C065166:imidapril; D009543:Nifedipine; D017298:Bisoprolol