Drug interaction for plasma protein binding: physostigmine and other drugs

Physostigmine (Phy) has gained prominence recently because of its use in the treatment of Alzheimer's disease and also as a prophylactic agent in the treatment of organophosphate intoxication. Since Alzheimer's disease is usually confined to the older population, the patients generally receive more than one medication. The present study examined whether Phy is displaced from the plasma protein binding site in vitro by a number of commonly prescribed drugs used in this patient population, using therapeutic range of blood levels. The binding of Phy to plasma proteins decreased in the presence of quinidine (3-15 micrograms/ml), from 45.5-5.3%, furosemide (1-100 micrograms/ml) from 45.5-28.4%, acetaminophen (10-160 micrograms/ml) 48.8-37.9%, theophylline (6.67-80 micrograms/ml) 52.2-43.7%, verapamil (0.1-0.5 micrograms/ml) 44.8-34.9%. However, imipramine (0.05-0.2 micrograms/ml), chlorpromazine (0.1-2 micrograms/ml) and propranolol (0.02-0.04 micrograms/ml) did not affect the binding of Phy irrespective of whether the plasma samples were preincubated with Phy or not. The binding of Phy to alpha 1-acid glycoprotein (50 mg/dl), gamma-globulin (1.3 mg/dl) and low density lipoprotein (0.83 mg/ml) was very small (less than 15%), contributing to about one-third of the total plasma protein binding. It appears that the binding of Phy to human plasma proteins was altered to a significant degree in the presence of quinidine, furosemide, acetaminophen, theophylline and verapamil. Free fraction of Phy in plasma has increased which could lead to greater toxicity of Phy.