Microdialysis Technology-based Pharmacokinetic Study On 6,8-substituted Quinoline And Its Metabolite In Rats

6,8-substituted quinoline(AM219)is a new anti-Alzheimer's disease drug with multi-targets,and its major metabolite(AM219B)in vivo is also an active compound of anti-Alzheimer's disease.The microdialysis sampling technology was used to study the pharmacokinetics of AM219 and its metabolite(AM219B)in rats.The recovery of microdialysis probes was studied and following results were obtained:When AM219 concentration was 2.5?g·ml-1 and flow rate was 1.0?l·min-1,the recoveries of blood probe for positive dialysis and retrodialysis of AM219 in vitro were(91.33 ± 1.14)%and(89.41±0.76)%,respectively;the recoveries of brain probe for positive dialysis and retrodialysis of AM219 in vitro were(59.91±1.14)%and(56.34±0.57)%,respectively;the recoveries of blood probe and brain probe for retrodialysis of AM219 in vivo were(52.72±5.6)%and(34.78±1.5)%,respectively.When AM219B concentration was 1.25?g·ml-1 and flow rate was 1.0?l·min-1,the recoveries of blood probe for positive dialysis and retrodialysis of AM219B in vitro were(68.63±1.31)%and(65.28±0.57)%,respectively;the recoveries of brain probe for positive dialysis and retrodialysis of AM219B in vitro were(58.73±1.25)%and(57.21±2.59)%,respectively;the recoveries of blood probe and brain probe for retrodialysis of AM219B in vivo were(35.79±1.90)%and(30.58±0.32)%,respectively.The LC-MS/MS methods were established to determine the content of AM219 and AM219B in plasma,blood dialysate and brain dialysate of rats.The pharmacokinetics of AM219 and its metabolite(AM219B)was stuied in rats with a dose of 25mg/kg i.v.and following results were obtained:AUC0-? values of AM219 and AM219B from plasma of rats were 447.74±149.59 mg/L·min and 392.14±71.35 mg/L·min,respectively.MRT values of AM219 and AM219B from plasma of rats were 91.75±17.07min and 171.84±18.83min,respectively.AUC0-? values of AM219 and AM219B from blood dialysate of rats were 147.16±50.97 mg/L·min and 264.76±65.60 mg/L·min,respectively.MRT values of AM219 and AM219B from blood dialysate of rats were 75.01±25.78min and 168.06±37.62min,respectively.AUC0-? values of AM219 and AM219B from brain dialysate of rats were 76.34±23.38 mg/L·min and 121.17±38.71 mg/L.min,respectively.MRT values of AM219 and AM219B from brain dialysate of rats were 56.82±13.30min and 173.78±8.26min,respectively.Both AM219 and its metabolite(AM219B)can bind to plasma protein,and AM219 has higher plasma protein binding rate than its metabolite.Their binding to plasma protein can decrease their concentration fluctuation and possible side effects,and prolong their biological half life.Both AM219 and its metabolite(AM219B)can pass through blood-brain barrier easily.AM219 can reach higher concentraition in brain in shorter time and AM219B can keep stable concentraition in brain for a long time.These pharmacokinetic properties can help them produce effect rapidly and steadily.