Chiang J, Oie S
Department of Pharmacy, School of Pharmacy, University of California, San Francisco.
J Pharmacol Exp Ther. 1990 Jul;254(1):324-9.
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.
一般认为，药物的药理反应与活性成分的游离浓度有关。然而，本研究报告称，在相同的游离浓度下，哌唑嗪的α1肾上腺素能阻断活性在有血浆蛋白α1酸性糖蛋白（AAG）存在时比不存在时要低。这一现象表明，血浆蛋白可通过游离分数值变化所反映机制以外的其他机制来改变药物活性。在对照大鼠和给予40mg/kg人AAG的大鼠中研究了哌唑嗪的药效学活性（收缩压降低百分比）。无论是静脉推注剂量（160μg/kg）后还是静脉输注期间（0.6 - 2.4μg/min/kg），在有AAG存在的情况下，效应与对数游离浓度的关系曲线均右移，即AAG降低了游离哌唑嗪的活性。在静脉推注研究中，对照动物中游离哌唑嗪的Emax和EC50（平均值±标准误）值分别为对照血压（零时间）的33.4±2.6%和6.2±1.4ng/ml；在接受AAG治疗的动物中分别为对照血压的37.8±6.0%和18.9±6.1ng/ml。在有AAG存在的情况下，EC50值有统计学显著升高（t = 4.97，P＜0.001），而Emax值未见差异（t = 1.65，P＞0.1）。文中讨论了AAG作用可能的潜在机制。
