College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766, USA.
College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766, USA; Department of Biology, California State Polytechnic University, Pomona, CA 91768, USA.
J Pharm Biomed Anal. 2018 May 10;153:37-43. doi: 10.1016/j.jpba.2018.01.009. Epub 2018 Feb 11.
Allosteric phosphodiesterase 4 (PDE4) inhibitors are highly sought after due to their important anti-inflammatory and anti-cancer therapeutic effects. We recently identified Eggmanone, an extraordinarily selective allosteric PDE4 inhibitor displaying favorable drug properties. However, a specific analytic method of Eggmanone in serum and its pharmacokinetics have not been reported yet. In this study, we developed a rapid and sensitive high performance liquid chromatography-mass spectrometric (HPLC-MS/MS) method to determine Eggmanone concentrations in rat plasma. This assay method was validated in terms of specificity, linearity, sensitivity, accuracy, precision, matrix effect, recovery and stability, and was applied to a pharmacokinetic study in rats following intravenous injection of Eggmanone at doses of 1 and 3 mg/kg. The lower limit of quantification (LLOQ) of this assay was 5 ng/mL and the linear calibration curve was acquired with R > 0.99 between 5 and 1000 ng/m. The intra-day and inter-day precision was evaluated with the coefficient of variations less than 11.09%, whereas the mean accuracy ranged from 98.38% to 105.13%. The assay method exhibited good recovery and negligible matrix effect. The samples were stable under all the experimental conditions. The plasma concentrations of Eggmanone were detected and quantified over 24 h with the terminal elimination half-live of 3.57 ± 1.80 h and 5.92 ± 3.34 h for the low dose (1 mg/kg) and high dose (3 mg/kg) respectively. In summary, the present method provides a robust, fast and sensitive analytical approach for quantification of Eggmanone in plasma and was successfully applied to a pharmacokinetic study in rats.
变构磷酸二酯酶 4（PDE4）抑制剂因其重要的抗炎和抗癌治疗效果而备受关注。我们最近发现了 Eggmanone，一种具有极好的变构 PDE4 选择性抑制剂，具有良好的药物特性。然而，尚未报道 Eggmanone 在血清中的特定分析方法及其药代动力学。在本研究中，我们开发了一种快速灵敏的高效液相色谱-质谱联用（HPLC-MS/MS）方法来测定大鼠血浆中的 Eggmanone 浓度。该测定方法在特异性、线性、灵敏度、准确性、精密度、基质效应、回收率和稳定性方面进行了验证，并应用于大鼠静脉注射 Eggmanone 1 和 3 mg/kg 后的药代动力学研究。该测定方法的定量下限（LLOQ）为 5 ng/mL，线性校准曲线在 5 至 1000 ng/mL 范围内获得，R > 0.99。日内和日间精密度用变异系数小于 11.09%进行评价，而平均准确度范围为 98.38%至 105.13%。该测定方法显示出良好的回收率和可忽略的基质效应。在所有实验条件下，样品均稳定。Eggmanone 的血浆浓度在 24 小时内被检测和定量，低剂量（1 mg/kg）和高剂量（3 mg/kg）的末端消除半衰期分别为 3.57±1.80 h 和 5.92±3.34 h。总之，本方法提供了一种强大、快速和灵敏的分析方法，用于定量测定血浆中的 Eggmanone，并成功应用于大鼠的药代动力学研究。
