Kwok D W, McErlane K M, Axelson J E
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Res Commun Chem Pathol Pharmacol. 1990 Mar;67(3):395-409.
Quantitation of tocainide carbamoyl-O-B-D-glucuronide, a major metabolite of the antiarrhythmic agent, tocainide, was previously reported using sodium hydroxide hydrolysis (pH greater than 12) of the glucuronide followed by gas chromatographic analysis of the hydrolyzed product, 3-(2',6'-xylyl)-5-methylhydantoin. In this investigation, the hydantoin was found to undergo rapid degradation during base hydrolysis of the tocainide glucuronide. The hydantoin was synthesized and its hydrolysis in sodium hydroxide (pH greater than 12) was found to follow first-order kinetics with an estimated half-life of 24.6 minutes. This spontaneous and rapid degradation of the hydantoin during hydrolysis of the tocainide glucuronide may result in underestimation of the hydantoin. To correct for the degradation of the hydantoin, a gas chromatographic assay with a timed, base-hydrolysis calibration protocol was designed. To demonstrate the applicability of this assay, the elimination kinetics of tocainide and the tocainide carbamoyl glucuronide were studied in three healthy male volunteers after a single 200 mg oral dose of tocainide hydrochloride. From urine data, the elimination half-life of tocainide was approximately 15.5 hours. The urinary excretion half-life of the tocainide carbamoyl glucuronide was approximately 13.8 hours.
抗心律失常药物妥卡尼的主要代谢产物妥卡尼氨甲酰 - O - β - D - 葡糖醛酸苷的定量分析，此前报道采用葡糖醛酸苷在氢氧化钠（pH大于12）中水解，随后对水解产物3 - (2',6'-二甲苯基)-5 - 甲基乙内酰脲进行气相色谱分析。在本研究中，发现乙内酰脲在妥卡尼葡糖醛酸苷的碱水解过程中会迅速降解。合成了乙内酰脲，并发现其在氢氧化钠（pH大于12）中的水解遵循一级动力学，估计半衰期为24.6分钟。妥卡尼葡糖醛酸苷水解过程中乙内酰脲的这种自发快速降解可能导致乙内酰脲的低估。为校正乙内酰脲的降解，设计了一种采用定时碱水解校准方案的气相色谱测定法。为证明该测定法的适用性，在三名健康男性志愿者单次口服200 mg盐酸妥卡尼后，研究了妥卡尼和妥卡尼氨甲酰葡糖醛酸苷的消除动力学。根据尿液数据，妥卡尼的消除半衰期约为15.5小时。妥卡尼氨甲酰葡糖醛酸苷的尿排泄半衰期约为13.8小时。
