Francotte E, Stierlin H, Faigle J W
J Chromatogr. 1985 Oct 18;346:321-31. doi: 10.1016/s0021-9673(00)90518-1.
The preparation of the optically pure enantiomers of the antiphlogistic trial drug oxindazac via liquid chromatographic resolution of the corresponding tert.-butyl or benzyl ester on triacetylcellulose is described. Cleavage of the optically pure enantiomeric esters to the acids proceeds without significant racemization. The methyl ester of oxindazac is also completely resolved on the same chiral phase. Whereas oxindazac racemizes easily upon derivatization to diastereomers, no racemization is observed upon methylation to the corresponding methyl ester with diazomethane. An inverse isotope dilution method has been developed to determine both enantiomers of the drug in biological fluids after administration of 14C-labelled oxindazac. The enantiomers are converted into their methyl esters and separated on triacetylcellulose. Quantitation is performed by on-line UV detection at 290 nm and off-line radiometry. In the analysis of plasma samples, endogenous compounds do not interfere. The recoveries of [14C]oxindazac from water, rat and human plasma were 99.6 +/- 1.8% for the (+/- and 96.0 +/- 1.4% for the (-)-enantiomer. The plasma concentrations and urinary excretion of the two enantiomers were determined in a human volunteer who had received 200 mg of racemic 14C-labelled oxindazac.
描述了通过在三乙酰纤维素上对相应的叔丁酯或苄酯进行液相色谱拆分来制备消炎试验药物奥辛达唑的光学纯对映体。将光学纯的对映体酯裂解为酸的过程中没有明显的消旋化。奥辛达唑的甲酯在相同的手性相上也能完全拆分。虽然奥辛达唑在衍生化为非对映体时很容易消旋，但在用重氮甲烷甲基化生成相应的甲酯时未观察到消旋化。已开发出一种反相同位素稀释法，用于在给予14C标记的奥辛达唑后测定生物流体中药物的两种对映体。将对映体转化为它们的甲酯，并在三乙酰纤维素上进行分离。通过在290nm处的在线紫外检测和离线放射性测定法进行定量。在血浆样品分析中，内源性化合物不产生干扰。从水、大鼠和人血浆中回收[14C]奥辛达唑，(+)-对映体为99.6±1.8%，(-)-对映体为96.0±1.4%。在一名接受200mg外消旋14C标记奥辛达唑的人类志愿者中测定了两种对映体的血浆浓度和尿排泄情况。
