National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
J Pharm Biomed Anal. 2012 Dec;71:119-26. doi: 10.1016/j.jpba.2012.08.022. Epub 2012 Aug 24.
Estrogen receptor (ER) subtype specific agonists, diarylpropionitrile (DPN) for ERβ and propylpyrazoletriol (PPT) for ERα, are pharmacological probes used frequently to define mechanisms for estrogen actions in vitro and in vivo. Quantitative analytical methodology was developed and validated for DPN and PPT, based on synthetic stable labeled analogs (DPN-d(4) and PPT-d(5)) using isotope dilution liquid chromatographic tandem electrospray mass spectrometric detection. The validated method produced high sensitivity, with detection limits of 0.04-0.07ng/ml serum. Serum pharmacokinetics were evaluated in Long-Evans rats following a single subcutaneous injection (2mg/kg bw) of both compounds. The role of Phase II metabolism was evaluated using β-glucuronidase and arylsulfatase hydrolysis to measure total DPN and PPT in addition to the parent compounds. The pharmacokinetic properties of DPN and PPT reported could facilitate experimental designs requiring specified levels of receptor occupancy for quantitative comparisons of ER subtype specificities for natural and synthetic estrogens in vivo.
雌激素受体（ER）亚型特异性激动剂，二芳基丙腈（DPN）用于 ERβ，丙基吡唑三醇（PPT）用于 ERα，是常用于体外和体内定义雌激素作用机制的药理学探针。基于合成的稳定标记类似物（DPN-d(4)和 PPT-d(5))，采用同位素稀释液相色谱串联电喷雾质谱检测法，为 DPN 和 PPT 开发并验证了定量分析方法。验证后的方法具有很高的灵敏度，血清检测限为 0.04-0.07ng/ml。在单次皮下注射（2mg/kg bw）两种化合物后，在长爪沙鼠中评估了血清药代动力学。使用β-葡萄糖醛酸酶和芳基硫酸酯酶水解来评估 II 相代谢的作用，以测量总 DPN 和 PPT 以及母体化合物。报告的 DPN 和 PPT 的药代动力学特性可以为需要特定受体占有率的实验设计提供便利，以便对天然和合成雌激素在体内的 ER 亚型特异性进行定量比较。
