Alteration of the pharmacokinetics and metabolism of propranolol and antipyrine elicited by indwelling catheters in the rat.
It has been shown that catheter implantation in rats increases concentrations of propranolol and this is usually explained by the increased serum protein binding of propranolol, as a consequence of the higher serum alpha-1-acid glycoprotein concentration. We investigated in this study whether this increase in propranolol concentration after p.o. administration is not also due to a decreased first pass metabolism. We therefore studied in rats the pharmacokinetics and the in vitro metabolism by hepatocytes, of propranolol and antipyrine, 2 and 48 hr after catheter implantation. After p.o. administration of propranolol, the area under the serum concentration time curve 48 hr after catheter implantation was increased 4-fold as compared to 2 hr. As the unbound propranolol fraction was decreased only by a factor of two, it can be concluded that the hepatic intrinsic clearance was decreased, and this was confirmed by a decreased metabolizing activity in the isolated hepatocytes of these animals. After i.v. administration of antipyrine, the systemic clearance was decreased, the volume of distribution was unchanged and the half-life was increased 48 hr after catheter implantation. As antipyrine is a low extraction drug and is not bound to serum proteins, the decreased systemic clearance suggests a lower hepatic intrinsic clearance, and this was again confirmed by a decreased metabolizing activity in the isolated hepatocytes. These results confirm the important effect of the presence of indwelling catheters on the serum concentrations of antipyrine and propranolol, and suggest that this effect is the result of both an increased serum binding and a decreased hepatic metabolism.
Heymans Institute of Pharmacology, University of Gent Medical School, Belgium.
B
B
Chindavijak
F M
FM
Belpaire
F
F
De Smet
M G
MG
Bogaert
D000818:Animals; D000983:Antipyrine / Q000378:metabolism / Q000493:pharmacokinetics*; D002408:Catheters, Indwelling; D008297:Male; D011433:Propranolol / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains
D011433:Propranolol; D000983:Antipyrine