title: Quantification of the calcium antagonism of lacidipine by kinetic analysis.
abstract: The calcium antagonist activity of the long-acting 1,4-dihydropyridine (DHP) lacidipine has been analyzed in rabbit basilar artery using a washout design in constant depolarizing conditions. From the kinetics of the loss of effect with washing, it was possible to fit a model that included the rate constant for dissociation of the DHP from the membrane (k-1) together with its affinity for the voltage-activated channel (K2). The k-1 values for lacidipine and two other DHPs (amlodipine and nifedipine) have been calculated as 0.0098, 0.0182 and 0.166 min-1, respectively. Assuming that the externally applied concentration of the DHP reflected the concentration in the membrane, the apparent pK2 values of 9.80, 9.0 and 9.25 were calculated for the three calcium antagonists. These values are in good agreement with those estimated in a previous study. When the partition of lacidipine into the membrane was taken into consideration, its apparent pK2 was reduced to 4.85. Thus, the study reinforces the concept that the high membrane partition of lacidipine contributes not only to its duration of action but also to its very high potency.
authors.affiliation: Glaxo Research Laboratories, Verona, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Giacometti
authors.forename: D
authors.initials: D
authors.lastname: Micheli
authors.forename: G
authors.initials: G
authors.lastname: Gaviraghi
authors.forename: D G
authors.initials: DG
authors.lastname: Trist
mesh_terms: D017311:Amlodipine / Q000493:pharmacokinetics; D000818:Animals; D001665:Binding Sites; D001825:Body Fluid Compartments; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics* / Q000494:pharmacology; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008432:Mathematical Computing; D008954:Models, Biological; D009124:Muscle Proteins / Q000378:metabolism; D011817:Rabbits
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D009124:Muscle Proteins; D017311:Amlodipine; C060285:lacidipine