Decreased elimination of unbound prazosin in the presence of alpha 1-acid glycoprotein in the rat in vivo.

The kinetics of unbound prazosin under constant i.v. infusion (800 ng/kg/min) and after i.v. bolus (160 micrograms/kg) were determined in control rats and in rats pretreated with human alpha 1-acid glycoprotein (AAG). Administration of 40 and 100 mg/kg of AAG decreased the unbound fraction in plasma of prazosin from 0.238 to 0.175 and 0.090, respectively. Administration of 40 mg/kg of AAG decreased the clearance of prazosin with respect to unbound drug (CLu) on the average by 40%. There was no statistically significant difference in the decrease of CLu between animals given constant infusions and i.v. bolus of prazosin. Increasing the administered dose of AAG from 40 to 100 mg/kg caused no further decrease in CLu. Because prazosin is a low-to-medium extraction ratio compound in the rat, this decrease in CLu indicates that AAG has an inhibitory effect on the elimination of prazosin that goes beyond a simple protein binding effect. The apparent volume of distribution of unbound drug, steady state, VUss, decreased from 12.4 to 7.7 liters/kg, and the red blood cell/plasma water concentration ratio decreased from 9.2 to 4.0 after administration of AAG. The possible mechanisms for the observed effects are discussed.