Pharmacologic activity of prazosin is decreased by alpha-1-acid glycoprotein in vivo.

The pharmacologic response to drugs is generally assumed to be related to the unbound concentration of the active species. This study, however, reports that the alpha-1 adrenergic blocking activity of prazosin is lower in the presence than in the absence of the plasma protein alpha-1-acid glycoprotein (AAG), at the same unbound concentrations. This phenomenon suggests that plasma proteins can modify the activity of drugs by mechanisms other than those reflected by changes in the unbound fraction values. The pharmacodynamic activity (percentage of decrease in systolic blood pressure) of prazosin was studied in control rats and in rats that were administered 40 mg/kg of human AAG. The effect vs. log unbound concentration relationships were right-shifted in the presence of AAG both after intravenous bolus doses (160 micrograms/kg) and during intravenous infusion (0.6-2.4 micrograms/min/kg), i.e., AAG decreased the activity of unbound prazosin. The Emax and EC50 (mean +/- S.E.) values for unbound prazosin in control animals in the intravenous bolus study were 33.4 +/- 2.6% of the control blood pressure (zero time) and 6.2 +/- 1.4 ng/ml, respectively; and in AAG-treated animals 37.8 +/- 6.0% of the control blood pressure and 18.9 +/- 6.1 ng/ml, respectively. The EC50 value was statistically significantly increased in the presence of AAG (t = 4.97, P less than .001) whereas no difference was seen in the Emax value (t = 1.65, P greater than .1). The possible underlying mechanism(s) of the effect of AAG is discussed.