呱氨托美丁及其代谢产物在大鼠体内药动学

Pharmacokinetics of amtolmetin guacil and its metabolites in rat

目的:研究呱氨托美丁(MED-15)单剂量灌胃给药及静脉注射在SD大鼠体内的药动学。方法:12只大鼠随机分为2组,分别灌胃给药MED-15(100mg.kg-1)或静脉注射MED-15(8mg.kg-1),采用HPLC法测定给药后大鼠血浆内MED-15代谢产物托美丁-甘氨酰胺衍生物(MED-5)及托美丁的浓度,应用DAS2.0软件进行非房室模型拟合及参数计算。结果:血样中未检测到MED-15,只能检测到其代谢产物MED-5及托美丁。灌胃组大鼠托美丁的Cmax为(2.8±1.1)mg.L-1,tmax为(7.9±1.1)h,AUC为(20.2±7.0)mg.h.L-1,静脉注射组大鼠托美丁的Cmax为(17.0±1.2)mg.L-1,AUC为(59.9±4.2)mg.h.L-1。结论:原药MED-15在大鼠胃肠道内有较强的首过代谢,导致生物利用度低。

OBJECTIVE To investigate the pharmacokinetics of amtolmetin guacil and its metabolites MED-5 and tolmetin after a single orally gavaged or intravenous injection of amtolmetin guacil in rats. METHODS A total of 12 SD rats were randomly divided into four groups and assigned to receive a single dose of 100 mg·kg^-1 （ig） and 8 mg.kg ^-1（iv） of amtolmetin guacil. HPLC was used for the determination of amtolmetin guacil and its metabolites in rat plasma. Pharmacokinetic parameters of these two rnetabolites were calculated by DAS 2.0 software （Non-compartment model）. RESULTS No amtolmetin guacil but its metabolites （MED-5 and tolmetin） were identified in the plasma of rats. The Cmax values of tolmetin was （2. 8 ± 1.1 ） mg.L^- 1, the tmax values was （7. 9 ± 1.1）h, and the AUC values was （20. 2 ± 7. 0） mg.h.L^-1 in ig group. The Cmax values of tolmetinwas（17.0±1.2） mg·L^-1, and the AUC values was （59. 9 ± 4. 2） mg·h·L^- 1 in iv group. CONCLUSION Thereis strong irst pass effect of MED-15 in gastrointestinal tract, and that may cause the low bioavailability of the drug.