Effect of Turpentine‐induced Inflammation on the Disposition Kinetics of Propranolol, Metoprolol, and Antipyrine in the Rat

Abstract

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 alpha 1-acid glycoprotein (alpha 1-AGP); metoprolol, another high extraction drug, but which is negligibly bound to alpha 1-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.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug‐disease interactions: reduced β‐adrenergic and potassium channel antagonist activities of sotalol in the presence of acute and chronic inflammatory conditions in the rat

“…The similar disposition of sotalol enantiomers in the healthy and in¯amed rats is due, perhaps, to negligible binding to plasma proteins and its complete (Anderson & Prystowsky, 1999). Hence, the two major in¯ammation-induced changes, i.e., increased serum a 1 -acid glycoproteins and decreased intrinsic hepatic clearance (Piafsky et al, 1978;Belpaire et al, 1989) do not play any signi®cant role in clearance of sotalol.…”

“…In¯ammation causes increased concentrations of a 1 -acid glycoproteins (Piafsky et al, 1978) and reduced intrinsic clearance (Belpaire et al, 1989), both of which can result in increased circulating drug concentration. This renders dierentiation between the eects due to pharmacodynamics changes and those resulting from pharmacokinetic alterations dicult.…”

Effect of Early Phase Adjuvant Arthritis on Hepatic P450 Enzymes and Pharmacokinetics of Verapamil: An Alternative Approach to the Use of an Animal Model of Inflammation for Pharmacokinetic Studies

“…AA-induced inflammation also results in increased levels of acute-phase proteins, impaired drug-metabolizing enzymes, and, consequently, reduced clearance of a variety of drugs (Walker et al, 1986;Belpaire et al, 1989;Pollock et al, 1989;Piquette-Miller and Jamali, 1993;Emami et al, 1998). Although a widely used model, AA is associated with excessive pain and discomfort.…”

“…Although this model of inflammation has been used extensively to study pharmacokinetics of drugs (Walker et al, 1986;Belpaire et al, 1989;Pollock et al, 1989;Piquette-Miller and Jamali, 1993;Emami et al, 1998), it subjects animals to significant pain (Nagakura et al, 2003). AA causes increased expression of proinflammatory mediators, which is associated with suppression of hepatic metabolic processes, and, hence, reduces clearance of efficiently cleared drugs (Piquette-Miller and Jamali, 1993;Morgan, 1997;Kulmatycki and Jamali, 2001).…”

Changes in mRNA expression of ABC and SLC transporters in liver and intestines of the adjuvant‐induced arthritis rat

“…Such inflammation-associated changes, which are collectively known as acute-phase responses, can result in profound increases in the plasma concentrations of various drugs, thereby causing toxic effects [1][2][3][4][5]. It was reported that cytochrome P-450 and chiral inversion activities are decreased in adjuvant-induced arthritis (AA) rats [6,7].…”