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Effect of congestive heart failure on clentiazem pharmacokinetics in a dog model
A K Laflamme1, G Caillé, R Cardinal
1Research Centre, Hôpital du Sacré-Coeur de Montréal, Canada.
Insights
Congestive heart failure significantly alters clentiazem pharmacokinetics in dogs. This calcium channel blocker
Area of Science:
- Pharmacology
- Cardiovascular Medicine
- Drug Metabolism
Background:
- Clentiazem (8-chloro diltiazem) is a calcium channel blocker investigated for stable angina and hypertension.
- Patients with ischemic disorders frequently have coexisting heart failure.
- Understanding drug behavior in heart failure is crucial for patient safety.
Purpose of the Study:
- To investigate the impact of congestive heart failure on clentiazem pharmacokinetics.
- To evaluate clentiazem disposition in a canine model of heart failure.
Main Methods:
- Congestive heart failure was induced in six dogs using rapid ventricular pacing.
- Clentiazem pharmacokinetics were assessed in control and heart failure states.
- Plasma concentrations were measured using high-performance liquid chromatography up to 480 minutes post-dose.
Main Results:
- Area under the curve (AUC0-infinity) for clentiazem significantly increased in heart failure dogs.
- Volume of distribution of the central compartment and total body clearance were reduced.
- These pharmacokinetic changes indicate altered clentiazem disposition.
Conclusions:
- Congestive heart failure significantly modifies clentiazem pharmacokinetics in this canine model.
- Caution is advised when administering clentiazem to patients with compromised cardiac function.
- Lower doses may be necessary for patients with severe congestive heart failure.
Abstract:
Clentiazem, 8-chloro diltiazem, is a calcium channel blocker currently undergoing evaluation for the treatment of stable angina and hypertension. As patients with ischaemic disorders often present some degree of heart failure, the aim of this study was to investigate the effect of congestive heart failure on clentiazem (200 micrograms kg-1, i.v. bolus) pharmacokinetics in a canine model. Congestive heart failure was induced in six dogs by rapid ventricular pacing (240 beats min-1) for 3-5 weeks. Clentiazem pharmacokinetics was studied in each dog under the control condition and after the development of clinical signs of heart failure (ascites, dyspnea, fatigue). Blood samples were collected up to 480 min post-dose. Clentiazem plasma concentrations were determined by high performance liquid chromatography. The area under the plasma concentration versus time curves (AUC0-infinity) was significantly increased in congestive heart failure dogs (8.8 +/- 1.6 vs 21.8 +/- 1.4 micrograms min ml-1) (mean +/- SEM). These changes were related to a reduction of the volume of distribution of the central compartment (0.9 +/- 0.1 vs 0.2 +/- 0.11 kg-1) and total body clearance (1.9 +/- 0.4 vs 0.7 +/- 0.21 h-1 kg-1). It is concluded that, in our model, congestive heart failure significantly modifies clentiazem disposition. These results suggest that caution should be exercised when clentiazem is given to patients with a low ejection fraction and a compromised cardiac function. Reduced loading and maintenance doses might be recommended in patients with severe congestive heart failure.