title: Pharmacodynamics and pharmacokinetics of clentiazem and diltiazem in closed-chest anesthetized dogs.
abstract: In the present study we investigated the relationship between pharmacodynamic and pharmacokinetic properties of the benzothiazepine-like calcium antagonists, clentiazem and diltiazem. Experiments were carried out in closed-chest anesthetized dogs, instrumented for hemodynamic recording and blood sampling. Clentiazem and diltiazem bolus injections (400 micrograms/kg) were administered intravenously, and subgroups of animals were sacrificed at 15, 30, 60, or 120 minutes Clentiazem and diltiazem plasma and myocardial levels were determined by high performance liquid chromatography (HPLC). Clentiazem elicited a more marked reduction in mean arterial pressure (-17% for clentiazem vs. -12% for diltiazem), along with an attenuation of the expected positive reflex chronotropic response. Pharmacokinetic analysis revealed that clentiazem had a greater volume of distribution (33 +/- 16 l vs. 15 +/- 9 l for diltiazem), while the half-life of elimination (t1/2 beta) was similar (55 +/- 21 minutes vs. 59 +/- 23 minutes). The kinetic disposition profile of both drugs was analyzed through myocardial/plasma concentration ratios. In the distribution phase (0-15 minutes), this ratio was similar (26 +/- 2 for clentiazem vs. 18 +/- 5 diltiazem), suggesting that the myocardium was not a preferential site of distribution for either drugs. Data collected within the elimination phase indicate significant myocardial retention for clentiazem; at the end of the study period, the myocardial/plasma concentration ratio was twofold higher for clentiazem. The observed retention of clentiazem in the myocardium may be responsible for attenuation of the baroreflex. Clentiazem increased potency was confirmed by the fact that its hypotensive and cardioinhibitory effects were observed at lower plasma concentrations.
authors.affiliation: Département de Pharmacologie, Faculté de Médecine, Université de Montréal, QC, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Giasson
authors.forename: D
authors.initials: D
authors.lastname: Garceau
authors.forename: W
authors.initials: W
authors.lastname: Homsy
authors.forename: L
authors.initials: L
authors.lastname: Dumont
mesh_terms: D000704:Analysis of Variance; D000768:Anesthesia, General; D000818:Animals; D017704:Baroreflex / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics / Q000494:pharmacology*; D002302:Cardiac Output / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D009206:Myocardium / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects; D014018:Tissue Distribution; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D002121:Calcium Channel Blockers; C056595:clentiazem; D004110:Diltiazem