Mathôt R A, Van den Aarsen B C, Soudijn W, Breimer D D, Ijzerman A P, Danhof M
Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, University of Leiden, The Netherlands.
J Pharmacol Exp Ther. 1995 Apr;273(1):405-14.
Recently, the commercially available adenosine receptor agonist S-N6-phenylisopropyladenosine (S-PIA) has been demonstrated to be contaminated with the more potent R-diastereomer. The potency of S-PIA may therefore have been overestimated in previously published in vivo studies. Our objective was to determine the potency of both diastereomers in conscious normotensive rats by using an integrated pharmacokinetic-pharmacodynamic model. In a cross-over designed study, the animals received i.v. infusions of 177 micrograms/kg (0.51 mumol/kg) R-N6-phenylisopropyladenosine (R-PIA) and 4000 micrograms/kg (11.6 mumol/kg) S-PIA. The infusion of S-PIA corresponded to a simultaneous administration of 3823 micrograms/kg (11.1 mumol/kg) and 177 micrograms/kg (0.51 mumol/kg) of the S- and R-diastereomer, respectively. During the experiment, time courses of heart rate and blood pressure were recorded continuously. Serial arterial blood samples were collected and concentrations were determined by using a stereoselective high-performance liquid chromatography assay. After administration of R-PIA, the individual concentration-effect relationships could be quantified by the sigmoidal Emax model, yielding an EC50 value of 24 +/- 3 ng/ml for the reduction in heart rate (mean +/- S.E., n = 12). After administration of S-PIA, a similar EC50 value was obtained when heart rate was correlated to concentrations of R-PIA. Modelling of the concentration-effect data according to a competitive interaction model did not yield pharmacodynamic parameter estimates for S-PIA. In conclusion, the cardiovascular effects observed after infusion of S-PIA may be attributed entirely to the presence of R-PIA.
最近，市售的腺苷受体激动剂S-N6-苯基异丙基腺苷（S-PIA）已被证明被更强效的R-非对映异构体污染。因此，S-PIA的效力在先前发表的体内研究中可能被高估了。我们的目的是通过使用整合的药代动力学-药效学模型来确定两种非对映异构体在清醒正常血压大鼠中的效力。在一项交叉设计研究中，动物接受静脉输注177微克/千克（0.51微摩尔/千克）的R-N6-苯基异丙基腺苷（R-PIA）和4000微克/千克（11.6微摩尔/千克）的S-PIA。S-PIA的输注分别相当于同时给予3823微克/千克（11.1微摩尔/千克）和177微克/千克（0.51微摩尔/千克）的S-和R-非对映异构体。在实验过程中，连续记录心率和血压的时间进程。采集系列动脉血样本，并使用立体选择性高效液相色谱法测定浓度。给予R-PIA后，个体浓度-效应关系可以通过S形Emax模型进行量化，心率降低的EC50值为24±3纳克/毫升（平均值±标准误，n = 12）。给予S-PIA后，当心率与R-PIA浓度相关时，获得了类似的EC50值。根据竞争性相互作用模型对浓度-效应数据进行建模，未得出S-PIA的药效学参数估计值。总之，输注S-PIA后观察到的心血管效应可能完全归因于R-PIA的存在。
