Effect of aging on the pharmcokinetics of atenolol, metoprolol and propranolol in the rat.
The pharmacokinetics of three beta adrenoceptor blocking drugs atenolol, metoprolol, propranolol and of the model drug antipyrine were studied in 3-, 12- and 24-month-old rats. Alpha-1-acid glycoprotein in plasma was slightly increased and the free fraction of propranolol was slightly decreased in the 24-month-old rats. For the four drugs studied, the volume of distribution and the clearance were decreased in the older rats. For propranolol, metoprolol and antipyrine these decreases were already observed in 12-month-old rats, for atenolol only in the 24-month-old rats. There was no change in half-life as a function of age for the three beta blockers; for antipyrine a significant increase in half-life was seen. The decreased volume of distribution suggests a lower tissue binding or a decrease in total body fluid. The change in clearance in function of age can probably be explained for metoprolol and propranolol by a decrease in hepatic blood flow as no change in metabolism or protein binding occurs, for atenolol by a decrease in renal function and for antipyrine by a decrease in metabolism. After p.o. administration of the beta blockers, no significant increase in area under the plasma drug concentration-time curve was observed for propranolol and metoprolol as a function of age, but for atenolol, a significant increase in area under the plasma drug concentration-time curve was seen in the 24-month-old rats, due to a decrease in renal function, as bioavailability of atenolol did not change in function of age.
Belpaire
F M
FM
Heymans Institute of Pharmacology, University of Gent Medical School, Belgium.
de Smet
F
F
Vynckier
L J
LJ
Vermeulen
A M
AM
Rosseel
M T
MT
Bogaert
M G
MG
Chauvelot-Moachon
L
L
D000375:Aging / Q000378:metabolism*; D000818:Animals; D000983:Antipyrine / Q000493:pharmacokinetics; D001262:Atenolol / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D008790:Metoprolol / Q000493:pharmacokinetics*; D009961:Orosomucoid / Q000032:analysis; D011433:Propranolol / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains
D009961:Orosomucoid; D001262:Atenolol; D011433:Propranolol; D008790:Metoprolol; D000983:Antipyrine