Effect of alpha 1-acidglycoprotein on myocardial uptake and pharmacodynamics of quinidine in perfused rat heart.
The myocardial uptake and pharmacodynamics of quinidine were examined in the isolated perfused rat heart preparation under conditions of varying concentrations of bovine alpha 1-acidglycoprotein (AAG) in the perfusate. Three hearts were perfused for five consecutive 35 min phases with buffer containing quinidine and AAG in concentrations of 0, 0.1, 0.5, 1.5 and 0 g/L, in that order, with a 55 min washout period between each phase. The equilibration rate constant for the quinidine output concentration increased with increasing AAG concentration, but not as much as predicted by the conventional pharmacokinetic uptake model, which assumes constant capillary permeability among the phases. Estimates of the permeability surface product for the two zero AAG phases (17.7 +/- 1.91 and 19.1 +/- 0.82 mL/min/g) were significantly greater than those for the three AAG phases (8.94 +/- 0.99, 8.70 +/- 0.26, 9.01 +/- 0.26 mL/min/g; P < 0.05). This effect of AAG is the same as that observed previously by us with bovine serum albumin in this same experimental preparation. This suggests that the mechanism of reduced capillary permeability is the same for both proteins, i.e., the formation of a steric barrier to paracellular transport rather than an electrostatic barrier. There was a direct, linear relationship between lengthening of the QT interval of the electrocardiogram and total and unbound quinidine concentrations, but the relationship for unbound concentration was independent of quinidine unbound fraction. Therefore, the electrocardiogram effect of quinidine was directly related to the circulating unbound rather than total drug concentration.
Huang
J L
JL
Department of Pharmaceutics, Victorian College of Pharmacy, Melbourne, Australia.
Morgan
D J
DJ
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009961:Orosomucoid / Q000494:pharmacology*; D010477:Perfusion; D011485:Protein Binding; D011802:Quinidine / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D009961:Orosomucoid; D011802:Quinidine