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ZJM-289, a novel nitric oxide-donating derivative of 3-n-butylphthalide, has been reported to alleviate cerebral ischemic-reperfusion injury in rats.In this study, we investigated the pharmacokinetic of ZJM-289 and 3-n-butylphthalide in rots following intravenous and intmgastric administration of ZJM-289.Following the intravenous dose, ZJM-289 was eliminated rapidly with a t1/2=19±4 min, CL and V calculated by non-compartmental analysis was 0.22+0.02 L/min/kg and 11.7+ 1.6 L/kg, respectively.AUC0-∝ increased in a dose-proportional manner from 80 to 320 mg/kg intragastric dose of ZJM-289.About 23% of ZJM-289 was converted to 3-n-butylphthalide.ZJM-289 degraded quickly in mouse and rat plasma (t1/2 =20.5-±-0.9, 24.3±0.9 min, respectively).Half-lives of ZJM-289 in microsomes were between 26 and 145 min(mouse < rat < beagle dog < monkey < human).Hydrolysis metabolites M1, M2, M3, M4 and M5, hydroxylation metabolite M6/M7, and glucuronide conjugate M8 were identified by LC-MS/MS in the liver and intestine microsomes.Kinetics of M4 formation in rat and mouse plasma fitted Michaelis-Menten equation and mediated by no more than one enzyme, while in liver microsomes as well as in rat intestine microsomes, M4 formation was mediated by more than one enzyme.The results from this study validated the pro-drug design hypothesis and pharmacological research.