Bauerová K
Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava.
Eur J Drug Metab Pharmacokinet. 1999 Jul-Sep;24(3):237-42. doi: 10.1007/BF03190026.
Besides its many pharmacodynamic actions, the pyridoindole stobadine was found to exert antioxidant activity and thus possesses the potential to protect various tissues against oxidative stress. This overview is focussed on both the evaluation of the chemical procedures used in the bioassay of stobadine and its metabolites and on the comparison of their quality in the light of applicability for preclinical and clinical pharmacokinetic experiments. All methods and applications were performed at the Institute of Experimental Pharmacology, SASc in Bratislava, Slovakia. In pharmacokinetic and toxicokinetic studies, [3H]-labeled stobadine dihydrochloride was administered intravenously or orally to rats in single and repeated doses. Liquid-liquid extraction was used for selective isolation of stobadine and its metabolites from biological matrix, followed by liquid scintillation quantification. A TLRC method was developed both to check the radiochemical purity of [3H]-stobadine and to quantify the labeled drug in rat plasma. A spectrofluorometric approach was used for determination of stobadine in dog serum and urine after its administration in the form of either the dihydrochloride or the dipalmitate. The method allowed us to perform a bioavailability study and a long-term toxicological study. The HPLC method with a limit of detection of 10 ng/ml of plasma proved suitable for calculating the compartmental pharmacokinetic parameters of both salt forms of stobadine administered to dog and man. This method was based on solid-phase extraction procedure by using Separcol SI C18 cartridges. In a GC method, the combination of capillary column separation and nitrogen-specific detection permitted the assay of serum stobadine concentrations as low as 5 ng/ml. The detection limit of the GC/MS method was 1 ng/ml of plasma or of phosphate buffer saline. This method was used for a bioequivalence study of two stobadine dipalmitate dosage forms and for a transdermal penetration study of stobadine acyl derivatives. All the developed assays proved to be appropriate for low-concentration determination of stobadine in a wide range of pharmacokinetic studies.
除了具有多种药效学作用外，吡啶并吲哚类药物司巴丁还具有抗氧化活性，因此有潜力保护各种组织免受氧化应激的影响。本综述聚焦于司巴丁及其代谢产物生物测定中所使用化学方法的评估，以及根据其在临床前和临床药代动力学实验中的适用性对其质量进行比较。所有方法和应用均在斯洛伐克布拉迪斯拉发的斯洛伐克科学院实验药理学研究所进行。在药代动力学和毒代动力学研究中，将[3H]标记的司巴丁二盐酸盐以单次和重复剂量静脉内或口服给予大鼠。液-液萃取用于从生物基质中选择性分离司巴丁及其代谢产物，随后进行液体闪烁定量分析。开发了一种TLRC方法，用于检查[3H] - 司巴丁的放射化学纯度并定量大鼠血浆中的标记药物。采用荧光分光光度法测定犬血清和尿液中以二盐酸盐或二棕榈酸盐形式给药后的司巴丁。该方法使我们能够进行生物利用度研究和长期毒理学研究。检测限为血浆10 ng/ml的HPLC方法被证明适用于计算给予犬和人的两种盐形式司巴丁的房室药代动力学参数。该方法基于使用Separcol SI C18柱的固相萃取程序。在气相色谱法中，毛细管柱分离和氮特异性检测相结合可测定低至5 ng/ml的血清司巴丁浓度。气相色谱/质谱法的检测限为血浆或磷酸盐缓冲盐水中的1 ng/ml。该方法用于两种司巴丁二棕榈酸酯剂型的生物等效性研究以及司巴丁酰基衍生物的透皮渗透研究。所有开发的分析方法都被证明适用于在广泛的药代动力学研究中低浓度测定司巴丁。
