Department of Medicinal Chemistry and Pharmacognosy, Jordan University of Science and Technology, Irbid, Jordan.
Int J Pharm. 2011 Sep 15;416(1):85-96. doi: 10.1016/j.ijpharm.2011.06.013. Epub 2011 Jun 15.
Five celecoxib (CXB) acylamide sodium salts, MP-CXB, Cy-CXB, Bz-CXB, CBz-CXB and FBz-CXB were synthesized and characterized. Two simple, fast and validated RP-HPLC methods were developed for simultaneous quantitative determination of the amides and celecoxib in aqueous and biological samples and LOD and LOQ were ≤13.6 and ≤40ng/mL, respectively. The solubility and logP(app) of the amides, in relevant media, were determined. The chemical hydrolysis, at 60, 70 and 80°C, of MP-CXB was studied at GIT-relevant pH (1.2, 6.8 and 7.4) and of CY-CXB was studied at skin relative pH (5.4 and 7.4). Significant hydrolysis was observed for MP-CXB at pH 1.2 only with half-lives 28.28, 11.64 and 3.53h at 60, 70 and 80°C, respectively, with extrapolated half-lives of 2060 and 443h at 25 and 37°C, respectively. The hydrolysis of all amides was studied in rat live homogenate and only Cy-CXB was hydrolyzed with half-life of 3.79h. The hydrolysis of MP-CXB and Cy-CXB was studied in human plasma and neither was hydrolyzed. It is finally suggested that hydrophobic interactions plays a role in the binding of susceptible acylamides to the hepatic hydrolyzing enzyme since only amides with saturated hydrocarbon chains underwent hydrolysis.
合成并表征了五种塞来昔布酰基酰胺钠盐，即 MP-CXB、Cy-CXB、Bz-CXB、CBz-CXB 和 FBz-CXB。建立了两种简单、快速且经过验证的反相高效液相色谱法，用于同时定量测定水相和生物样品中的酰胺和塞来昔布，检测限和定量限分别为≤13.6 和≤40ng/mL。测定了酰胺在相关介质中的溶解度和 logP(app)。在 GIT 相关 pH（1.2、6.8 和 7.4）下研究了 MP-CXB 的化学水解，在皮肤相关 pH（5.4 和 7.4）下研究了 Cy-CXB 的化学水解。仅在 pH 1.2 下观察到 MP-CXB 发生显著水解，60、70 和 80°C 下的半衰期分别为 28.28、11.64 和 3.53h，25 和 37°C 下的推测半衰期分别为 2060 和 443h。在大鼠活体匀浆中研究了所有酰胺的水解，只有 Cy-CXB 发生水解，半衰期为 3.79h。在人血浆中研究了 MP-CXB 和 Cy-CXB 的水解，两者均未发生水解。最后建议疏水性相互作用在易水解酰基酰胺与肝水解酶的结合中起作用，因为只有具有饱和烃链的酰胺发生水解。
