EFFECT OF TURPENTINE-INDUCED INFLAMMATION ON THE DISPOSITION KINETICS OF PROPRANOLOL, METOPROLOL, AND ANTIPYRINE IN THE RAT

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Abstract
Summary— Plasma concentrations after oral administration of the high extraction drug propranolol are increased in patients and animals with inflammation. This could be due to increased serum propranolol binding, but also to decreased first-pass metabolism. We studied the pharmacokinetics of 3 drugs in control rats and in rats with turpentine-induced inflammation: propranolol, which is bound extensively to α1-acid glycoprotein (α1-AGP); metoprolol, another high extraction drug, but which is negligibly bound to α1-AGP; and antipyrine, a low extraction drug, not bound to serum proteins. After IV administration of propranolol in rats with inflammation, systemic clearance, volume of distribution, and free fraction decreased, and the area under the curve (AUC) increased, whereas the half-life did not change. As the systemic clearance of a high extraction drug such as propranolol depends on hepatic blood flow only, a fall in hepatic blood flow or transition to a low extraction situation should be postulated. After oral administration of propranolol, the AUC was increased 20-fold in rats with inflammation; as the decrease in free fraction was only 4-fold, it can be concluded that a considerable decrease in hepatic intrinsic clearance was present. For metoprolol, in contrast to propranolol, after IV administration, no changes in pharmacokinetic parameters as a result of inflammation were observed. After oral administration, the AUC was increased about 4 times in rats with inflammation; as metoprolol is only negligibly bound to serum proteins, the increase in AUC can be attributed to a decrease in hepatic intrinsic clearance. The differential effect of turpentine on the intravenous kinetics of propranolol and metoprolol can be explained by the fact that propranolol binding is increased by turpentine treatment. For antipyrine, systemic clearance was decreased, the volume of distribution was unchanged, and the half-life was increased in the turpentine-treated rats. As antipyrine is not bound in serum, one can conclude that its hepatic intrinsic clearance was decreased. Inflammation induced by turpentine treatment decreases the metabolism of high and low extraction drugs.