Increased Plasma Protein Binding of Propranolol and Chlorpromazine Mediated by Disease-Induced Elevations of Plasma α₁Acid Glycoprotein

Abstract

To assess the importance of disease-induced increases in plasma concentrations of alpha1 acid glycoprotein (an acute-phase plasma protein that binds cationic drugs), we determined binding of propranolol in plasma from 53 patients and 25 healthy volunteers. Binding was increased in 10 patients with Crohn's disease (P less than 0.002), nine with inflammatory arthritis (P less than 0.002) and eight with chronic renal failure with superimposed inflammatory disease (P less than 0.01) as compared with healthy controls. The plasma binding of control subjects did not differ from that of 12 patients with chronic hepatic disease (P greater than 0.45) or 14 with uncomplicated renal failure (P greater than 0.80). Chlorpromazine binding, determined in 60 subjects, yielded similar results. Percentage of free drug and alpha1 acid glycoprotein concentration were inversely correlated (r = -0.77 with propranolol, P less than 0.001, and r = -0.69 with chlorpromazine, P less than 0.001). Increases in plasma protein binding in patients with inflammatory disease appear mediated by increases in alpha1 acid glycoprotein concentration, which may influence drug kinetics.

Orosomucoid Serum Concentrations and Fat Depot-Specific mRNA and Protein Expression in Humans

“…In humans, circulating ORM levels have been widely studied and the levels have been reported to fluctuate due to disease states (Jackson et al, 1982;Piafsky et al, 1978) and stress (Edwards et al, 1982). As an acute phase protein, ORM is synthesized mainly by the liver, but extrahepatic synthesis has also been reported (Fournier et al, 2000).…”

The plasma protein binding of basic drugs.

“…It often contributes significantly towards the total binding of basic drugs in plasma. Fifty percent of the propranolol found in plasma is bound to albumin for example (Bel- Table 1 Some basic drugs which bind significantly to a,-acid glycoprotein (AAG) /3-adrenoceptor blockers Alprenolol (Piafsky & Borga, 1977) Oxprenolol Pindolol Propranolol (Piafsky et al, 1978) Timolol Miscellaneous Chlorpromazine (Piafsky et al, 1978) Dipyridamole (Kopitar & Weisenberger, 1971) Erythromycin (Prandota et al, 1980) Metoclopramide (Webb et al, 1986) Nicardipine (Urien et al, 1985) Phencyclidine (Giles et al, 1982) Prednisolone (Milsap & Jusko, 1983) Progesterone (Ganguly & Westphal, 1968) Triazolam (Kobroth et al, 1984) paire et al, 1982). Since albumin tends to show low affinity high capacity binding of basic drugs it is unusual for variation in albumin concentrations to result in marked changes in their plasma protein binding.…”

Acute-Phase Proteins: Alpha -1- Acid Glycoprotein

“…Increases in plasma protein binding in patients with inflammatory disease appear mediated by increases in α 1 acid glycoprotein concentration, which may influence drug kinetics. [37] The AAG levels' variations have implications for the monitoring of the free fractions of basic drugs during clinical therapy. The consequences of elevated serum AGP levels, often seen in several disease states, on the pharmacokinetic of drugs have been investigated using transgenic animals.…”

“…In addition, these animals demonstrated a significant decrease in the percent of lidocaine binding in the mandible. [57] Drug Drug Characteristics elevated AAG dependent activity lidocaine antiarrythmic total plasma lidocaine cumulation [55][56][57][58] propranolol beta blocker reduced unbound propranolol fraction [37] imipramine antidepressant reduced free drug fraction [48] disopyramide antiarrhythmic reduced free drug fraction [50] phenytoin antiepileptic reduced free drug fraction [47] paclitaxel cancer medication reduced free drug fraction [49] Moreover role of stress (trauma, cold swimming, and adjuvant rheumatoid arthritis) on lidocaine concentrations as well as lidocaine's protein binding in heart and liver tissues in male Wistar rats was investigated. Since lidocaine is a cationic molecule it is bound to AGP.…”