Zhang Shuqiu, Xing Jie, Zhong Dafang
Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110015, People's Republic of China.
J Pharm Sci. 2004 May;93(5):1300-9. doi: 10.1002/jps.20023.
The biotransformation of roxithromycin in simulated gastrointestinal fluids at 37 degrees C and in rats was investigated by using liquid chromatography-tandem mass spectrometry. Roxithromycin degraded to its Z-isomer and decladinose derivative in simulated gastrointestinal fluids in vitro at pH </= 3, and followed pseudo first-order degradation with a rate constant (+/-SD, standard derivation) of 0.1066 min(-1) (+/-0.0014) at pH 1.0, 0.0994 min(-1) (+/-0.0031) at pH 1.2, 0.0400 min(-1) (+/-0.0003) at pH 1.3, 0.0136 min(-1) (+/-0.0008) at pH 1.8, and 0.0022 min(-1) (+/-0.0002) at pH 3.0, respectively. The ratio of Z-roxithromycin to roxithromycin (+/-SD) was 0.21 (+/-0.01) at pH 1.0, 0.19 (+/-0.03) at pH 1.2, 0.18 (+/-0.01) at pH 1.3, 0.15 (+/-0.01) at pH 1.8, and 0.08 (+/-0.02) at pH 3.0, respectively. Pepsin and NaCl added to gastric fluid had no effect on the transformation of roxithromycin. Roxithromycin underwent four metabolic routes such as geometric isomerization, demethylation, dealkylation, and hydrolysis of cladinose in rats after oral administration. The geometric isomerization in rats was neither observed after an intravenous dose, nor after an oral dose with Na(2)CO(3) alkalization. The geometric isomerization between roxithromycin and its Z-isomer took place in gastric fluid both in vitro and in vivo. It was interconvertible and pH-dependent. The isomerization of roxithromycin to its Z-isomer was less than that of Z- to E-configuration both in vitro and in vivo.
采用液相色谱 - 串联质谱法研究了罗红霉素在37℃模拟胃肠液及大鼠体内的生物转化情况。罗红霉素在体外pH≤3的模拟胃肠液中降解为其Z - 异构体和去克拉定糖衍生物，在pH 1.0时遵循假一级降解，速率常数（±标准差）为0.1066 min⁻¹（±0.0014），在pH 1.2时为0.0994 min⁻¹（±0.0031），在pH 1.3时为0.0400 min⁻¹（±0.0003），在pH 1.8时为0.0136 min⁻¹（±0.0008），在pH 3.0时为0.0022 min⁻¹（±0.0002）。Z - 罗红霉素与罗红霉素的比例（±标准差）在pH 1.0时为0.21（±0.01），在pH 1.2时为0.19（±0.03），在pH 1.3时为0.18（±0.01），在pH 1.8时为0.15（±0.01），在pH 3.0时为0.08（±0.02）。向胃液中添加胃蛋白酶和氯化钠对罗红霉素的转化没有影响。口服给药后，罗红霉素在大鼠体内经历了几何异构化、去甲基化、脱烷基化和克拉定糖水解等四条代谢途径。静脉给药后以及口服碳酸钠碱化后的大鼠体内均未观察到几何异构化现象。罗红霉素与其Z - 异构体之间的几何异构化在体外和体内的胃液中均会发生。它是可相互转化且依赖于pH的。罗红霉素向其Z - 异构体的异构化在体外和体内均小于Z - 到E - 构型的异构化。
