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Effect of congestive heart failure on clentiazem pharmacokinetics in a dog model
Author(s) -
K.Laflamme Annik,
Caillé Gilles,
Cardinal René,
Croteau Daniel,
Lamoureux Claudette,
Lambert Chantal
Publication year - 1992
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2510130705
Subject(s) - heart failure , medicine , diltiazem , ejection fraction , cardiology , pharmacokinetics , bolus (digestion) , calcium
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 μg 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 (AUC 0−∞ ) was significantly increased in congestive heart failure dogs (8·8 ± 1·6 vs 21·8 ± 1·4 μg 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 ± 0·1 1kg −1 ) and total body clearance (1·9 ± 0·4 vs 0·7 ± 0·2 1h −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.