Influence of albumin on isoprenaline and propranolol effects on isolated rat uterus.
We investigated the effect of albumin (6%) on the (+/-)-isoprenaline-induced relaxation of strips of isolated rat uterus and its antagonism by (-)-propranolol. The mean isoprenaline EC50 in the presence of albumin was significantly less than that in the absence of albumin (geometric mean 1.94 +/- 3.33 versus 3.21 +/- 3.50 nM, respectively; n = 14; p = 0.006, paired t test). This indicates enhancement of isoprenaline activity by albumin which could not be explained by protein binding, as this would have reduced activity. Geometric mean control KB values for inhibition of isoprenaline by propranolol at 26.8 and 500 nM were 0.835 +/- 1.68 (n = 10) and 0.889 +/- 1.60 nM (n = 34), respectively. In the presence of 6% albumin, KB for propranolol was increased significantly to 13.3 +/- 1.8 nM (n = 27, p < 0.001). Calculation of KB in terms of the measured propranolol unbound concentration of 26.8 nM, after taking into account the lower isoprenaline EC50 in the presence of albumin, yielded a mean value of 0.725 +/- 1.86 nM, which was not significantly different from either control (p > 0.05). Therefore, propranolol activity was as predicted by the unbound drug concentration in contrast to isoprenaline activity. We conclude that albumin can alter in vitro drug activity by mechanisms in addition to the reduction of unbound drug concentration.
Morgan
D J
DJ
Victorian College of Pharmacy, Monash University, Melbourne, Australia.
Richmond
B H
BH
Malta
E
E
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007700:Kinetics; D009126:Muscle Relaxation / Q000187:drug effects; D011433:Propranolol / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000378:metabolism / Q000494:pharmacology*; D014590:Uterine Contraction / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
D012710:Serum Albumin, Bovine; D011433:Propranolol; D007545:Isoproterenol