Biliary excretion and enterohepatic circulation of thienorphine and its glucuronide conjugate in rats

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.

Gut-liver axis plays a role in hepatocarcinogenesis of patients with Crohn's disease

The development of hepatocellular carcinoma （HCC） is attributed to several factors, including chronic viral infection, alcohol consumption, exposure to aflatoxin 131 and metabolic disorders. Several recent reports have shown that HCC can occur in patients with longstanding Crohn＇s disease （CD） in the absence of other underlying high-risk liver diseases. There may be an association between CD and hepatocarcinogenesis, however, the precise mechanism for this requires further investigations.

Changes of gastrointestinal myoelectric activity and bile acid pool size after cholecystectomy in guinea pigs

AIM: To investigate the bile acid pool size after cholecystectomy whether or not correlated to the gastrointestinal migrating myoeiectric complex (MMC) in guinea pigs. METHODS: Gallbladder motilities were assessed before cholecystectomy. Furthermore, we continuously monitored interdigestive gastrointestinal motilities using bipolar electrodes in conscious guinea pigs before and after surgery at 4 wk in standard diet group and high cholesterol diet (cholesterol gallstone) group. Total bile acid pool sizes were measured by isotope dilution method at meantime. RESULTS: After cholecystectomy, there were parallel falls in duration of phase Ⅰ, Ⅱ, Ⅲ and MMC cycle duration but increase in amplitude in the guinea pigs with normal gallbladder function, and in the guinea pigs with cholesterol stones. However, There were not significantly differences. On the other hand, the bile acid pool was definitely small in the GS guinea pigs compared to normal guinea pigs and became slightly smaller after cholecystectomy. Similarly, bile acid in gallbladder bile, fecal bile acid was slightly increased in GS guinea pigs after cholecystectomy, to the same degree as normal. These differences, however, were not significant. CONCLUSION: It is concluded that in the guinea pigs with normal gallbladder function, and in the guinea pigs with cholesterol stones: (1) Cholecystectomy produce a similar but less marked trend in bile acid pool; and (2) MMC are linked to enterohepatic circulation of bile acids, rather than surgery, which is consistent with changes of the bile acid pool size. As a result, gastrointestinal dyskinesia is not involved in occurrence of postchole cystectomy syndrome.

The role of bile acids in human aging

Bile acids are recognized as important signaling molecules that enable fine-tuned inter-communication from the liver,through the intestine,to virtually any organ,thus encouraging their pleiotropic physiological effects.Aging is a complex natural process defined as a progressive decline in cellular and organismal functions.A causal link between bile acids and the aging process is emerging.However,there are gaps in our understanding of the molecular mechanisms and precise targets responsible for the alteration of bile acid profiles and their role in the aging process.Intestinal barrier dysfunction leads to endotoxemia,systemic inflammation,insulin resistance,diabetes,lipid accumulation,obesity and fatty liver diseases,and health decline and death.In fact,intestinal barrier dysfunction is suggested to be an evolutionarily conserved hallmark of aging.Bile acids may modulate the aging process by regulating intestinal barrier integrity.

Changes of gastrointestinal myoelectric activity and bile acid pool during cholesterol gallstone formation in guinea pig

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？