Thienorphine(TNP)is a new partial opioid agonist currently developed as a promising drug candidate with the intended clinical indication for the treatment of opioid dependence.The pharmacokinetic profile and biliary e...Thienorphine(TNP)is a new partial opioid agonist currently developed as a promising drug candidate with the intended clinical indication for the treatment of opioid dependence.The pharmacokinetic profile and biliary excretion of TNP and its glucuronide conjugate(TNP-Glu)were investigated after oral administration of TNP in rats.The concentrations of TNP and TNP-Glu were simultaneously quantified using a LC-MS/MS method.A double peak phenomenon was observed in TNP plasma concentration–time curves with the secondary peak appeared at 6–8 h.A slower decline of plasma concentrations in the terminal phase was observed for TNP with T1/2 of 7.01 h.TNP-Glu was the predominant component in rat plasma and bile.Its plasma level was about 10 times higher than TNP and the 24 h accumulative bile excretion rate was 23%.Enterohepatic circulation of TNP and TNP-Glu was evaluated using a paired rat model.In bile-donor rats,no double-peak was detected and the elimination half life of TNP was significantly shortened(3.71 h)when compared to intact rats(7.01 h,P<0.05).Both TNP and TNP-Glu were detected in bile-recipient rats.Their exposures in recipient rats due to enterohepatic circulation were 15.6%and 42.6%for the parent drug and the metabolite,respectively.The deconjugation of the glucuronide conjugate and the reabsorption of free TNP were further confirmed in in situ perfused rat intestinal preparations.These results indicate that the enterohepatic circulation has a significant influence on the systemic exposure of the parent drug and its glucuronide conjugate,particularly on the terminal elimination of TNP,which may result in the prolonged retention of the drug in body.展开更多
It has been known that enterohepatic circulation of bile acids is essential for regular cycling of migrating motor complex （MMC）. An important component of the enterohepatic circulation is the active reabsorption of...It has been known that enterohepatic circulation of bile acids is essential for regular cycling of migrating motor complex （MMC）. An important component of the enterohepatic circulation is the active reabsorption of conjugated bile acids in the terminal ileum, with special reference to bile acid pool size that may be defined as the total mass of bile acids in the enterohepatic circulation. However, because of technical difficulties in measuring of bile acid pool size in human being, the role of the bile acid pool has little been investigated, and the exact mechanism of change in bile acid pool size has not yet been clear. Therefore, were there two changes of small intestinal motility and bile acid pool size in cholesterol gallstone patients？ and, if so, was there correlated relationship between both alterations require further investigation？展开更多
基金supported by Chinese National S&T Major Special Project on Major New Drug Innovation(Grant numbers:2009ZX09301-002 and 2011ZX09101-005-01).
文摘Thienorphine(TNP)is a new partial opioid agonist currently developed as a promising drug candidate with the intended clinical indication for the treatment of opioid dependence.The pharmacokinetic profile and biliary excretion of TNP and its glucuronide conjugate(TNP-Glu)were investigated after oral administration of TNP in rats.The concentrations of TNP and TNP-Glu were simultaneously quantified using a LC-MS/MS method.A double peak phenomenon was observed in TNP plasma concentration–time curves with the secondary peak appeared at 6–8 h.A slower decline of plasma concentrations in the terminal phase was observed for TNP with T1/2 of 7.01 h.TNP-Glu was the predominant component in rat plasma and bile.Its plasma level was about 10 times higher than TNP and the 24 h accumulative bile excretion rate was 23%.Enterohepatic circulation of TNP and TNP-Glu was evaluated using a paired rat model.In bile-donor rats,no double-peak was detected and the elimination half life of TNP was significantly shortened(3.71 h)when compared to intact rats(7.01 h,P<0.05).Both TNP and TNP-Glu were detected in bile-recipient rats.Their exposures in recipient rats due to enterohepatic circulation were 15.6%and 42.6%for the parent drug and the metabolite,respectively.The deconjugation of the glucuronide conjugate and the reabsorption of free TNP were further confirmed in in situ perfused rat intestinal preparations.These results indicate that the enterohepatic circulation has a significant influence on the systemic exposure of the parent drug and its glucuronide conjugate,particularly on the terminal elimination of TNP,which may result in the prolonged retention of the drug in body.
文摘It has been known that enterohepatic circulation of bile acids is essential for regular cycling of migrating motor complex （MMC）. An important component of the enterohepatic circulation is the active reabsorption of conjugated bile acids in the terminal ileum, with special reference to bile acid pool size that may be defined as the total mass of bile acids in the enterohepatic circulation. However, because of technical difficulties in measuring of bile acid pool size in human being, the role of the bile acid pool has little been investigated, and the exact mechanism of change in bile acid pool size has not yet been clear. Therefore, were there two changes of small intestinal motility and bile acid pool size in cholesterol gallstone patients？ and, if so, was there correlated relationship between both alterations require further investigation？
